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Sample records for antagonizes icp4-dependent silencing

  1. Silence multiple

    DEFF Research Database (Denmark)

    Søndergaard, Katia Dupret

    -Network Theoretical approach to organization studies silence is conceptualised as both a means and an effect of innovative efforts. It is a way of ordering practices. Thus silencing is thought of as a central potential change agent both in composing a kind of specific organizational collectivity and in composing new...

  2. Silencing the city?

    OpenAIRE

    Jean-Paul Thibaud; Pascal Amphoux

    2013-01-01

    The notion of silence must be handled very carefully. In addition, its use reveals the way we deal with the urban environment as well as social life. What does the notion of silence convey about the current state of the urban sonic environment? How can we clarify the various meanings and the stakes involved in silence? Three themes are developed in order to answer these questions: silence as a research topic presents three complementary perspectives (acoustic, sociocultural, technological); s...

  3. Dramaturgy and Silence.

    Science.gov (United States)

    Proehl, Geoffrey S.

    2003-01-01

    Notes that in rehearsals and performances, a jumble of silences are encountered. Discusses silence in the following situations: as frustration; as imposition; as invisibility; as power; as pleasure; as safety; as humility; as necessity; and as potential. Contends that when dramaturgs enter into conversation and break silence, they must carefully…

  4. Silencing the city?

    Directory of Open Access Journals (Sweden)

    Jean-Paul Thibaud

    2013-12-01

    Full Text Available The notion of silence must be handled very carefully. In addition, its use reveals the way we deal with the urban environment as well as social life. What does the notion of silence convey about the current state of the urban sonic environment? How can we clarify the various meanings and the stakes involved in silence? Three themes are developed in order to answer these questions: silence as a research topic presents three complementary perspectives (acoustic, sociocultural, technological; silence as a polysemous notion emphasises the ideas of keeping quiet, tranquillity and pause; silence as a design issue relies on basic properties and principles in order to orient the design of the urban sonic environment.

  5. Uncompetitive antagonism of AMPA receptors

    DEFF Research Database (Denmark)

    Andersen, Trine F; Tikhonov, Denis B; Bølcho, Ulrik;

    2006-01-01

    Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. ...... polyamine toxins antagonize the AMPA receptor ion channel and provide the basis for rational development of uncompetitive antagonists of AMPA receptors....

  6. Ombuds’ corner: Employee silence

    CERN Multimedia

    Vincent Vuillemin

    2013-01-01

    Although around a hundred cases a year are reported to the Ombuds, several issues may still not be disclosed due to employee silence*. The deliberate withholding of concerns, escalating misunderstandings or genuine conflicts can impede the global process of learning and development of a better respectful organizational workplace environment, and prevent the detection and correction of acts violating the CERN Code of Conduct.   For the employee him/herself, such silence can lead to feelings of anger, resentment, helplessness and humiliation. These feelings will inevitably contaminate personal and interpersonal relations, and poison creativity and effectiveness. Employee silence can be explained by many factors; sometimes it is connected to organizational forces. In their published paper*, authors Michael Knoll and Rolf van Dick found four forms of employee silence. People may stay silent if they feel that their opinion is neither welcomed nor valued by their management. They have gi...

  7. Stabilizing membrane domains antagonizes anesthesia

    CERN Document Server

    Machta, Benjamin B; Nouri, Mariam; McCarthy, Nicola L C; Gray, Erin M; Miller, Ann L; Brooks, Nicholas J; Veatch, Sarah L

    2016-01-01

    Diverse molecules induce general anesthesia with potency strongly correlated both with their hydrophobicity and their effects on certain ion channels. We recently observed that several anesthetics inhibit heterogeneity in plasma membrane derived vesicles by lowering the critical temperature ($T_c$) for phase separation. Here we exploit conditions that stabilize membrane heterogeneity to test the correlation between the anesthetic potency of n-alcohols and effects on $T_c$. First we show that hexadecanol acts oppositely to anesthetics on membrane mixing and antagonizes ethanol induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described `intoxication reversers' raise $T_c$ in vesicles and counter ethanol's effects in vesicles, mimicking the findings of previous electrophysiological measurements. Third, we find that hydrostatic pressure, long known to reverse anesthesia, also raises $T_c$ in vesicles with a magnitude that counters the effect of an anesthetic at relevant concen...

  8. Breaking the Silence

    Institute of Scientific and Technical Information of China (English)

    1998-01-01

    Many women who suffer from vaginitis have kept silent about their illness because they think it is shameful to have such a disease. The International Women’s Health Coalition (IWHC) has publicized the problem, referring to it as a "culture of silence"inherited from traditional thinking. The coalition has made attempts to improve women’s health conditions by changing people’s misconceptions about the disease. In 1997, under a grant from the American Ford Foundation, the Sichuan Provincial Women’s Federation carried out a study on women’s repro-ductive health, aimed at "breaking the silence."

  9. Memories Persist in Silence

    Directory of Open Access Journals (Sweden)

    Sandra Patricia Arenas Grisales

    2012-08-01

    Full Text Available This article exposes the hypothesis that memory artifacts, created to commemorate the victims of armed conflict in Colombia, are an expression of the underground memories and a way of political action in the midst of war. We analyze three cases of creations of memory artifacts in Medellín, Colombia, as forms of suffering, perceiving and resisting the power of armed groups in Medellín. The silence, inherent in these objects, should not be treated as an absence of language, but as another form of expression of memory. Silence is a tactic used to overcome losses and reset everyday life in contexts of protracted violence.

  10. Sexual and parental antagonism shape genomic architecture

    OpenAIRE

    Patten, Manus M.; Úbeda, Francisco; Haig, David

    2013-01-01

    Populations with two sexes are vulnerable to a pair of genetic conflicts: sexual antagonism that can arise when alleles have opposing fitness effects on females and males; and parental antagonism that arises when alleles have opposing fitness effects when maternally and paternally inherited. This paper extends previous theoretical work that found stable linkage disequilibrium (LD) between sexually antagonistic loci. We find that LD is also generated between parentally antagonistic loci, and b...

  11. Illuminating employees’ organizational silence

    Directory of Open Access Journals (Sweden)

    Jaber Moghaddampour

    2013-08-01

    Full Text Available Undoubtedly, human capital is the main source of knowledge generation, which leads to a competitive advantage and sustainability of organizations. When managers pay more attention to such capital, they will be able to lead their organization, more effectively. In such route, the managers should look for their employees’ opinions on policies/plans of the organization and learn how to run the organization and organizational challenges. They should use their employees’ knowledge to improve the quality of decisions, they should encourage them to share their ideas and protect them from organizational silence. Thus, human capitals will be obviously considered as strategic capitals of an organization. Concerning the importance of organizational sound, the status of organizational silence is studied in 13 selected organizations in Qom Province – as one the biggest Iranian provinces. The findings indicate that organizational silence in Qom selected organizations is not in an ideal status and the current level should be mitigated. Likewise, findings show that there is no significant difference between organizational silence in Qom selected organizations in terms of demographic variables.

  12. The Silence of Michelangelo

    DEFF Research Database (Denmark)

    Foote, Jonathan

    2016-01-01

    of contemplation with Ovid's well-known myth of Pygmalion. Similarly, while sojourning in the Carrara quarries in 1516, he ignored repeated requests from the pope, friends and family to send a model for the facade of San Lorenzo. The silence from papal politics notwithstanding, it was in fact the hammering...

  13. A combinatorial code for splicing silencing: UAGG and GGGG motifs.

    Directory of Open Access Journals (Sweden)

    Kyoungha Han

    2005-05-01

    Full Text Available Alternative pre-mRNA splicing is widely used to regulate gene expression by tuning the levels of tissue-specific mRNA isoforms. Few regulatory mechanisms are understood at the level of combinatorial control despite numerous sequences, distinct from splice sites, that have been shown to play roles in splicing enhancement or silencing. Here we use molecular approaches to identify a ternary combination of exonic UAGG and 5'-splice-site-proximal GGGG motifs that functions cooperatively to silence the brain-region-specific CI cassette exon (exon 19 of the glutamate NMDA R1 receptor (GRIN1 transcript. Disruption of three components of the motif pattern converted the CI cassette into a constitutive exon, while predominant skipping was conferred when the same components were introduced, de novo, into a heterologous constitutive exon. Predominant exon silencing was directed by the motif pattern in the presence of six competing exonic splicing enhancers, and this effect was retained after systematically repositioning the two exonic UAGGs within the CI cassette. In this system, hnRNP A1 was shown to mediate silencing while hnRNP H antagonized silencing. Genome-wide computational analysis combined with RT-PCR testing showed that a class of skipped human and mouse exons can be identified by searches that preserve the sequence and spatial configuration of the UAGG and GGGG motifs. This analysis suggests that the multi-component silencing code may play an important role in the tissue-specific regulation of the CI cassette exon, and that it may serve more generally as a molecular language to allow for intricate adjustments and the coordination of splicing patterns from different genes.

  14. The Conspiracy Of Silence

    OpenAIRE

    Cohen, Saul

    1980-01-01

    The issue of the impaired physician is compounded by not only mass denial of the problem, but also a 'conspiracy of silence' among many groups associated with the physician. The conspirators—including the physician himself, his family, community, professional colleagues and nurses as well as hospital boards and administration—are unable to reconcile deteriorating performance due to alcohol or drugs with an otherwise gifted professional who should know the dangers of substance abuse. They may ...

  15. Silence in Intercultural communication

    Institute of Scientific and Technical Information of China (English)

    Guo Jun

    2012-01-01

    In communication, most of people's attention focuses on verbal communication, nonverbal language as a means of exchange is often ignored. However, nonverbal language continues sending signals, and most of these signals are sent to conversational partners unconsciously. So correct understanding of these signals will help people improve effectiveness of communication. This article will focus on silence, a major part of nonverbal communication, exploring its communicative functions and cultural differences.

  16. Silence in the Communication or Communicating through Silence: Silence in Psychoanalysis

    Directory of Open Access Journals (Sweden)

    Rita Marta

    2014-10-01

    Full Text Available This paper is a reflection upon the meaning and importance of silence in the psychoanalytical relationship. Beginning with the silence in the “normal” relationship between people, we show how silence can be experienced as confortable or unconfortable, and how it can be used to achieve a bigger proximity or distance in the relationship with others. We show these same aspects in the psychoanalytical relationship, and the evolution of the regard towards silence along the development of psychoanalysis. We end, presenting the Nacht’s thinking about silence, who emphasizes its integrative and fundamental role in the psychoanalytical relationship. Thus, only through silence certain affects can be born, and silence allows the patient to internalize the analyst.

  17. Antisense gene silencing

    DEFF Research Database (Denmark)

    Nielsen, Troels T; Nielsen, Jørgen E

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied...... to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how...

  18. Breaking the silence

    DEFF Research Database (Denmark)

    Konradsen, Hanne; Kirkevold, Marit; McCallin, Antoinette;

    2012-01-01

    and individual interviews were analyzed using the grounded theory method. The findings revealed that the main concern of the patients was feeling isolated, which was resolved using a process of interactional integration. Interactional integration begins by breaking the silence to enable the progression from......Little is known about the psychosocial effects of facial disfigurement. We present the results of a qualitative study following 15 patients who had been surgically treated for head, neck, or eye cancer over the course of their first postoperative year. Taped nurse-patient conversations...

  19. Bodies, Spaces, Voices, Silences

    Directory of Open Access Journals (Sweden)

    Donatella Mazzoleni

    2013-07-01

    Full Text Available A good architecture should not only allow functional, formal and technical quality for urban spaces, but also let the voice of the city be perceived, listened, enjoyed. Every city has got its specific sound identity, or “ISO” (R. O. Benenzon, made up of a complex texture of background noises and fluctuation of sound figures emerging and disappearing in a game of continuous fadings. For instance, the ISO of Naples is characterized by a spread need of hearing the sound return of one’s/others voices, by a hate of silence. Cities may fall ill: illness from noise, within super-crowded neighbourhoods, or illness from silence, in the forced isolation of peripheries. The proposal of an urban music therapy denotes an unpublished and innovative enlarged interdisciplinary research path, where architecture, music, medicine, psychology, communication science may converge, in order to work for rebalancing spaces and relation life of the urban collectivity, through the care of body and sound dimensions.

  20. Edwin Hubble's Silence

    Science.gov (United States)

    Lago, D.

    2013-04-01

    In late 1928 Edwin Hubble was right in the middle of using V. M. Slipher's redshift data to prove that the universe is expanding, when Hubble's boss, George Hale, directed him to drop everything and rush to the Grand Canyon and test it as a possible site for Hale's planned 200-inch telescope. On his way, Hubble stopped at Lowell Observatory and met with V. M. Slipher. The letters both men wrote about this visit suggest that Hubble never said a word about his being in the middle of using Slipher's research to transform the universe. At the least, this silence is symbolic of the silence with which astronomical history has often treated Slipher's work. A survey of the historical literature suggests several reasons for this. Theorists and observers in astronomy (and other sciences) have long had different perspectives about how science works, and those who place more importance on theory have tended to credit the idea of the expanding universe to the theorists. Also, many sources indicate that Edwin Hubble was not a modest man or generous about sharing credit.

  1. Triclosan antagonizes fluconazole activity against Candida albicans.

    LENUS (Irish Health Repository)

    Higgins, J

    2012-01-01

    Triclosan is a broad-spectrum antimicrobial compound commonly used in oral hygiene products. Investigation of its activity against Candida albicans showed that triclosan was fungicidal at concentrations of 16 mg\\/L. However, at subinhibitory concentrations (0.5-2 mg\\/L), triclosan antagonized the activity of fluconazole. Although triclosan induced CDR1 expression in C. albicans, antagonism was still observed in cdr1Δ and cdr2Δ strains. Triclosan did not affect fluconazole uptake or alter total membrane sterol content, but did induce the expression of FAS1 and FAS2, indicating that its mode of action may involve inhibition of fatty acid synthesis, as it does in prokaryotes. However, FAS2 mutants did not exhibit increased susceptibility to triclosan, and overexpression of both FAS1 and FAS2 alleles did not alter triclosan susceptibility. Unexpectedly, the antagonistic effect was specific for C. albicans under hypha-inducing conditions and was absent in the non-filamentous efg1Δ strain. This antagonism may be due to the membranotropic activity of triclosan and the unique composition of hyphal membranes.

  2. RNA silencing movement in plants

    Institute of Scientific and Technical Information of China (English)

    Glykeria Mermigka; Frederic Verret; Kriton Kalantidis

    2016-01-01

    Multicellular organisms, like higher plants, need to coordinate their growth and development and to cope with environmental cues. To achieve this, various signal molecules are transported between neighboring cells and distant organs to control the fate of the recipient cells and organs. RNA silencing produces cell non-autonomous signal molecules that can move over short or long distances leading to the sequence specific silencing of a target gene in a well defined area of cells or throughout the entire plant, respectively. The nature of these signal molecules, the route of silencing spread, and the genes involved in their production, movement and reception are discussed in this review. Additionally, a short section on features of silencing spread in animal models is presented at the end of this review.

  3. Offeree silence and contractual agreement.

    OpenAIRE

    Austen-Baker, Richard

    2006-01-01

    This article considers the mechanics of acceptance in the law of contract, focusing on the question of whether the silence of an offeree can effect acceptance. It finds the rule in Felthouse v Bindley (1862) alive and well, but creating problems for judges anxious to find agreements in place. The article considers whether there is, as sometimes suggested, a ‘duty to speak’ and dismisses this, along with any other supposed exceptions to the rule, concluding that silence cannot effect acceptanc...

  4. Natural Protection of Wood with Antagonism Fungi

    Directory of Open Access Journals (Sweden)

    Alba ZAREMSKI

    2011-03-01

    Full Text Available Biological environments contain a certain number of microbial populations which, within a givenecological niche, display various relations ranging from symbiosis to parasitism. Researchers have beeninterested in these types of relations for around fifty years, especially in one very particular type ofrelationship: the antagonism exerted between individuals of the same microbial population.Today, the role played by biological agents, bringing into play inhibitive or destructive antibioticsubstances, reveals a certain potential for their use in controlling microorganisms associated with suchdegradation processes.The work undertaken by HydroQuébec and CIRAD involved two types of experiment: 1 in Petri dishes toassess and characterize the antagonistic capacity of Trichoderma against white rot and brown rot fungi; 2on pieces taken from untreated poles in order to study confrontation between the basidiomycete and theantagonistic strain in wood.This study investigated the antagonism of three ascomycetes of the genus Trichoderma against two whiterot basidiomycetes, Pycnoporus sanguineus and Coriolus versicolor, and two brown rot basidiomycetes,Antrodia sp. and Coniophora puteana, through direct confrontation in Petri dishes and in the wood ofHydroQuébec poles.The results obtained seemed to complete each other coherently. They revealed that the Trichodermagroup of fungi was not aggressive to wood and the results obtained after direct confrontation in Petri disheswere confirmed in wood.By directly exposing the different basidiomycetes and antagonists to each other in Petri dishes, two bytwo, we effectively revealed an antagonism effect for a large majority of the pairs. However, there wassubstantial variability in reactions from one pair to the next.

  5. [Antagonism of lactobacilli, oral streptococci and staphylococci].

    Science.gov (United States)

    Chervinets, Iu V; Beliaeva, E A; Ganina, E B; Troshin, A V; Chervinets, A V

    2015-01-01

    From the oral cavity of healthy young people aged 18-22 years there were isolated 26 strains of lactobacilli, 28 streptococci, including the pathogenic and opportunistic strains, and 32 strains of staphylococci, 10 of which were methicillin-resistant S.aureus. Oral lactobacilli possessed by a high probiotic potential, showing high antagonism to methicillin-resistant staphylococci, pathogenic and opportunistic streptococci and enterococci. Oral lactobacilli showed medium and high adhesive activity that determines their high adaptive capacity. Staphylococci and streptococci in 90.3% of cases have not an antagonistic effect on lactobacilli. Isolated lactobacilli can be used as probiotic strains for oral administration.

  6. Identification and mechanism of ABA receptor antagonism

    KAUST Repository

    Melcher, Karsten

    2010-08-22

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands. © 2010 Nature America, Inc. All rights reserved.

  7. WIF1 is a frequent target for epigenetic silencing in squamous cell carcinoma of the cervix

    OpenAIRE

    Delmas, Amber L.; Riggs, Bridget M; Pardo, Carolina E.; Dyer, Lisa M.; Darst, Russell P.; Izumchenko, Eugene G.; Monroe, Mänette; Hakam, Ardeshir; Kladde, Michael P.; Erin M Siegel; Brown, Kevin D.

    2011-01-01

    Aberrant activation of the Wnt/β-catenin signaling axis is a prominent oncogenic mechanism in numerous cancers including cervical cancer. Wnt inhibitory factor-1 (WIF1) is a secreted protein that binds Wnt and antagonizes Wnt activity. While the WIF1 gene is characterized as a target for epigenetic silencing in some tumor types, WIF1 expression has not been examined in human cervical tissue and cervical cancer. Here, we show that WIF1 is unmethylated and its gene product is expressed in norma...

  8. Transcriptional Silencing of Retroviral Vectors

    DEFF Research Database (Denmark)

    Lund, Anders Henrik; Duch, M.; Pedersen, F.S.

    1996-01-01

    . Extinction of long-term vector expression has been observed after implantation of transduced hematopoietic cells as well as fibroblasts, myoblasts and hepatocytes. Here we review the influence of vector structure, integration site and cell type on transcriptional silencing. While down-regulation of proviral...... transcription is known from a number of cellular and animal models, major insight has been gained from studies in the germ line and embryonal cells of the mouse. Key elements for the transfer and expression of retroviral vectors, such as the viral transcriptional enhancer and the binding site for the t......RNA primer for reverse transcription may have a major influence on transcriptional silencing. Alterations of these elements of the vector backbone as well as the use of internal promoter elements from housekeeping genes may contribute to reduce transcriptional silencing. The use of cell culture and animal...

  9. Rotavirus Antagonism of the Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Michelle M. Arnold

    2009-11-01

    Full Text Available Rotavirus is a primary cause of severe dehydrating gastroenteritis in infants and young children. The virus is sensitive to the antiviral effects triggered by the interferon (IFN-signaling pathway, an important component of the host cell innate immune response. To counteract these effects, rotavirus encodes a nonstructural protein (NSP1 that induces the degradation of proteins involved in regulating IFN expression, such as members of the IFN regulatory factor (IRF family. In some instances, NSP1 also subverts IFN expression by causing the degradation of a component of the E3 ubiquitin ligase complex responsible for activating NF-κB. By antagonizing multiple components of the IFN-induction pathway, NSP1 aids viral spread and contributes to rotavirus pathogenesis.

  10. Agonism and antagonism at the insulin receptor

    DEFF Research Database (Denmark)

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia;

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new...... insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been...... shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR...

  11. Diverse chromatin remodeling genes antagonize the Rb-involved SynMuv pathways in C. elegans.

    Directory of Open Access Journals (Sweden)

    Mingxue Cui

    2006-05-01

    Full Text Available In Caenorhabditis elegans, vulval cell-fate specification involves the activities of multiple signal transduction and regulatory pathways that include a receptor tyrosine kinase/Ras/mitogen-activated protein kinase pathway and synthetic multivulva (SynMuv pathways. Many genes in the SynMuv pathways encode transcription factors including the homologs of mammalian Rb, E2F, and components of the nucleosome-remodeling deacetylase complex. To further elucidate the functions of the SynMuv genes, we performed a genome-wide RNA interference (RNAi screen to search for genes that antagonize the SynMuv gene activities. Among those that displayed a varying degree of suppression of the SynMuv phenotype, 32 genes are potentially involved in chromatin remodeling (called SynMuv suppressor genes herein. Genetic mutations of two representative genes (zfp-1 and mes-4 were used to further characterize their positive roles in vulval induction and relationships with Ras function. Our analysis revealed antagonistic roles of the SynMuv suppressor genes and the SynMuv B genes in germline-soma distinction, RNAi, somatic transgene silencing, and tissue specific expression of pgl-1 and the lag-2/Delta genes. The opposite roles of these SynMuv B and SynMuv suppressor genes on transcriptional regulation were confirmed in somatic transgene silencing. We also report the identifications of ten new genes in the RNAi pathway and six new genes in germline silencing. Among the ten new RNAi genes, three encode homologs of proteins involved in both protein degradation and chromatin remodeling. Our findings suggest that multiple chromatin remodeling complexes are involved in regulating the expression of specific genes that play critical roles in developmental decisions.

  12. Communicative Silences: Forms and Functions

    Science.gov (United States)

    Bruneau, Thomas J.

    1973-01-01

    The nature of silence is discussed as an imposition of mind, as an interdependent signification ground for speech signs, as a relationship to mental time (as opposed to artificial time), and as it relates to sensation, perception and metaphorical movement. (Author)

  13. Silence in the creative process

    Directory of Open Access Journals (Sweden)

    Francesco Wilhelm

    2015-01-01

    Full Text Available A research about silence as the moment where creative thinking takes place, as an art object and as a way of interpreting artworks, is the main issue of the graduation thesis named Il silenzio nel processo creativo (2014. Here is proposed an offprint, which summarizes its fundamental steps.

  14. Polycomb complexes and silencing mechanisms

    DEFF Research Database (Denmark)

    Lund, Anders H; van Lohuizen, Maarten

    2004-01-01

    Advances in the past couple of years have brought important new knowledge on the mechanisms by which Polycomb-group proteins regulate gene expression and on the consequences of their actions. The discovery of histone methylation imprints specific for Polycomb and Trithorax complexes has provided...... mechanistic insight on how this ancient epigenetic memory system acts to repress and indicates that it may share mechanistic aspects with other silencing and genome-protective processes, such as RNA interference....

  15. Polymyxin B antagonizing biological activity of lipopolysaccharide

    Institute of Scientific and Technical Information of China (English)

    GUO Yi-bin; CHEN Li-ping; CAO Hong-wei; WANG Ning; ZHENG Jiang; XIAO Guang-xia

    2007-01-01

    Objective: To investigate the mechanism of polymyxin B (PMB) antagonizing the biological activity of lipopolysaccharide (LPS). Methods: The affinity of PMB for LPS and lipid A was assayed by biosensor, and the neutralization of PMB for LPS(2 ng/ml) was detected by kinetic turbidimetric limulus test. The releases of TNF-α and IL-6 in murine peritoneal macrophages (PMψ) after exposure to LPS (100 ng/ml) were detected, and the expression levels of TLR4, TNF-α and IL-6 mRNA in PMψ induced by LPS (100 ng/ml) were measured by RT-PCR. Results: PMB had high-affinity to LPS and lipid A with dissociation equilibrium constants of 18.9 nmol/L and 11.1 nmol/L, respectively, and neutralized LPS in a dose-dependent manner. Furthermore, PMB could markedly inhibit the expressions of TLR4, TNF-α and IL-6 mRNA and the release of cycokines in LPS-stimulated murine PMψ.Conclusions: PMB neutralizes LPS and inhibites the expression and release of cycokines in macrophages, in which the affinity of PMB for lipid A plays an important role.

  16. A Strategy for Antagonizing Quorum Sensing

    Energy Technology Data Exchange (ETDEWEB)

    G Chen; L Swem; D Swem; D Stauff; C OLoughlin; P Jeffrey; B Bassler; F Hughson

    2011-12-31

    Quorum-sensing bacteria communicate via small molecules called autoinducers to coordinate collective behaviors. Because quorum sensing controls virulence factor expression in many clinically relevant pathogens, membrane-permeable quorum sensing antagonists that prevent population-wide expression of virulence genes offer a potential route to novel antibacterial therapeutics. Here, we report a strategy for inhibiting quorum-sensing receptors of the widespread LuxR family. Structure-function studies with natural and synthetic ligands demonstrate that the dimeric LuxR-type transcription factor CviR from Chromobacterium violaceum is potently antagonized by molecules that bind in place of the native acylated homoserine lactone autoinducer, provided that they stabilize a closed conformation. In such conformations, each of the two DNA-binding domains interacts with the ligand-binding domain of the opposing monomer. Consequently, the DNA-binding helices are held apart by {approx}60 {angstrom}, twice the {approx}30 {angstrom} separation required for operator binding. This approach may represent a general strategy for the inhibition of multidomain proteins.

  17. Tat RNA silencing suppressor activity contributes to perturbation of lymphocyte miRNA by HIV-1

    Directory of Open Access Journals (Sweden)

    Yu Lianbo

    2011-05-01

    Full Text Available Abstract Background MicroRNA (miRNA-mediated RNA silencing is integral to virtually every cellular process including cell cycle progression and response to virus infection. The interplay between RNA silencing and HIV-1 is multifaceted, and accumulating evidence posits a strike-counterstrike interface that alters the cellular environment to favor virus replication. For instance, miRNA-mediated RNA silencing of HIV-1 translation is antagonized by HIV-1 Tat RNA silencing suppressor activity. The activity of HIV-1 accessory proteins Vpr/Vif delays cell cycle progression, which is a process prominently modulated by miRNA. The expression profile of cellular miRNA is altered by HIV-1 infection in both cultured cells and clinical samples. The open question stands of what, if any, is the contribution of Tat RNA silencing suppressor activity or Vpr/Vif activity to the perturbation of cellular miRNA by HIV-1. Results Herein, we compared the perturbation of miRNA expression profiles of lymphocytes infected with HIV-1NL4-3 or derivative strains that are deficient in Tat RNA silencing suppressor activity (Tat K51A substitution or ablated of the vpr/vif open reading frames. Microarrays recapitulated the perturbation of the cellular miRNA profile by HIV-1 infection. The miRNA expression trends overlapped ~50% with published microarray results on clinical samples from HIV-1 infected patients. Moreover, the number of miRNA perturbed by HIV-1 was largely similar despite ablation of Tat RSS activity and Vpr/Vif; however, the Tat RSS mutation lessened HIV-1 downregulation of twenty-two miRNAs. Conclusions Our study identified miRNA expression changes attributable to Tat RSS activity in HIV-1NL4-3. The results accomplish a necessary step in the process to understand the interface of HIV-1 with host RNA silencing activity. The overlap in miRNA expression trends observed between HIV-1 infected CEMx174 lymphocytes and primary cells supports the utility of cultured

  18. RDR2 partially antagonizes the production of RDR6-dependent siRNA in sense transgene-mediated PTGS.

    Directory of Open Access Journals (Sweden)

    Vincent Jauvion

    Full Text Available BACKGROUND: RNA-DEPENDENT RNA POLYMERASE6 (RDR6 and SUPPRESSOR of GENE SILENCING 3 (SGS3 are required for DNA methylation and post-transcriptional gene silencing (PTGS mediated by 21-nt siRNAs produced by sense transgenes (S-PTGS. In contrast, RDR2, but not RDR6, is required for DNA methylation and TGS mediated by 24-nt siRNAs, and for cell-to-cell spreading of IR-PTGS mediated by 21-nt siRNAs produced by inverted repeat transgenes under the control of a phloem-specific promoter. PRINCIPAL FINDINGS: In this study, we examined the role of RDR2 and RDR6 in S-PTGS. Unlike RDR6, RDR2 is not required for DNA methylation of transgenes subjected to S-PTGS. RDR6 is essential for the production of siRNAs by transgenes subjected to S-PTGS, but RDR2 also contributes to the production of transgene siRNAs when RDR6 is present because rdr2 mutations reduce transgene siRNA accumulation. However, the siRNAs produced via RDR2 likely are counteractive in wildtype plants because impairement of RDR2 increases S-PTGS efficiency at a transgenic locus that triggers limited silencing, and accelerates S-PTGS at a transgenic locus that triggers efficient silencing. CONCLUSIONS/SIGNIFICANCE: These results suggest that RDR2 and RDR6 compete for RNA substrates produced by transgenes subjected to S-PTGS. RDR2 partially antagonizes RDR6 because RDR2 action likely results in the production of counteractive siRNA. As a result, S-PTGS efficiency is increased in rdr2 mutants.

  19. [A gun silencer of a special kind].

    Science.gov (United States)

    Schyma, C; Schyma, P; Milbradt, H

    2000-01-01

    The authors report about a small bore pistol with silencer. In addition, the silencer can be sealed up by a rubber plate. This leads to a false estimation of the shooting distance. Also at close range shots the shot with the silencer and the rubber seal leaves hardly gunshot residues. The bullet wipe persists but microradiography shows his changed morphological composition. The use of the rubber seal leads predominantly to atypical bullet holes. PMID:10829239

  20. [E. M. Jellinek's silenced and silencing transgenerational story].

    Science.gov (United States)

    Kelemen, Gábor; Márk, Mónika

    2013-01-01

    Jellinek is a kind of archetypal character for future generations in the field of addiction studies. His implosion in the arena of alcoholism around the age of 50 was an unexpected challenge to medical science. We know very little about his own role models giving an intellectual and moral compass to his pragmatic creativity. More than 30 years has passed since Jellinek's death when an American sociologist Ron Roizen started unearthing his silent story. Roizen discerned that there are a lot of unsaid and muted issues in his personal Hungarian past. Our paper, based on the authors' research in Hungarian archives and other sources reveals that not just Jellinek's personal but his transgenerational narrative has been not-yet-said. This silenced and silencing history appears an unfinished business of acculturation of the family, which started prior to four generations. Authors have been concluding that the issue of religious conversion is a critical point in the process of acculturation. They examine the counter move of loyalty to family values and driving force of assimilation making their story unspeakable.

  1. [E. M. Jellinek's silenced and silencing transgenerational story].

    Science.gov (United States)

    Kelemen, Gábor; Márk, Mónika

    2013-01-01

    Jellinek is a kind of archetypal character for future generations in the field of addiction studies. His implosion in the arena of alcoholism around the age of 50 was an unexpected challenge to medical science. We know very little about his own role models giving an intellectual and moral compass to his pragmatic creativity. More than 30 years has passed since Jellinek's death when an American sociologist Ron Roizen started unearthing his silent story. Roizen discerned that there are a lot of unsaid and muted issues in his personal Hungarian past. Our paper, based on the authors' research in Hungarian archives and other sources reveals that not just Jellinek's personal but his transgenerational narrative has been not-yet-said. This silenced and silencing history appears an unfinished business of acculturation of the family, which started prior to four generations. Authors have been concluding that the issue of religious conversion is a critical point in the process of acculturation. They examine the counter move of loyalty to family values and driving force of assimilation making their story unspeakable. PMID:24443572

  2. Mechanisms guiding Polycomb activities during gene silencing in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Chongsheng eHe

    2013-11-01

    Full Text Available Polycomb group (PcG proteins act in an evolutionarily conserved epigenetic pathway that regulates chromatin structures in plants and animals, repressing many developmentally important genes by modifying histones. PcG proteins can form at least two multiprotein complexes: Polycomb repressive complexes 1 and 2 (PRC1 and PRC2, respectively. The functions of Arabidopsis thaliana PRCs have been characterized in multiple stages of development and have diverse roles in response to environmental stimuli. Recently, the mechanism that precisely regulates Arabidopsis PcG activity was extensively studied. In this review, we summarize recent discoveries in the regulations of PcG at the three different layers: the recruitment of PRCs to specific target loci, the polyubiquitination and degradation of PRC2, and the antagonism of PRC2 activity by the Trithorax group proteins. Current knowledge indicates that the powerful activity of the PcG pathway is strictly controlled for specific silencing of target genes during plant development and in response to environmental stimuli.

  3. Silence in Cross-cultural Communication

    Institute of Scientific and Technical Information of China (English)

    常利娜; 郭芳芳; 郝继亭; 顾庆媛; 孙胜强

    2008-01-01

    In academic field, silence is classified as part of the nonverbal communication. Edward T. Hall regarded silence as a key standard of dividing high-context cultures and low-context cultures (毕 46). In high-context cultures, information is provided through gestures, the use of space, and even silence. Little information is explicitly explained by words. Chinese, Japanese, Native American cultures are high-context ones. However, "in low-context cultures, the verbal message contains most of the information and very little is embedded in the context." (Samovar, A. Larry, Richard E. Porter and Lisa A. Stefani 79). How do people from different cultures respond to silence? How their values affect their attitudes? What causes silence?

  4. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    Directory of Open Access Journals (Sweden)

    Yun-Liang Cui

    2016-01-01

    Conclusions: The rhubarb mixture of emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid, 1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl-β-D-glucose, daucosterol linoleate, and rhein, at a low concentration, antagonized the MMP9-induced HUVEC monolayer permeability by promoting HUVEC proliferation and reducing extracellular VE-cadherin concentrations.

  5. Exploitative and hierarchical antagonism in a cooperative bacterium.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Social organisms that cooperate with some members of their own species, such as close relatives, may fail to cooperate with other genotypes of the same species. Such noncooperation may take the form of outright antagonism or social exploitation. Myxococcus xanthus is a highly social prokaryote that cooperatively develops into spore-bearing, multicellular fruiting bodies in response to starvation. Here we have characterized the nature of social interactions among nine developmentally proficient strains of M. xanthus isolated from spatially distant locations. Strains were competed against one another in all possible pairwise combinations during starvation-induced development. In most pairings, at least one competitor exhibited strong antagonism toward its partner and a majority of mixes showed bidirectional antagonism that decreased total spore production, even to the point of driving whole populations to extinction. Differential response to mixing was the primary determinant of competitive superiority rather than the sporulation efficiencies of unmixed populations. In some competitive pairings, the dominant partner sporulated more efficiently in mixed populations than in clonal isolation. This finding represents a novel form of exploitation in bacteria carried out by socially competent genotypes and is the first documentation of social exploitation among natural bacterial isolates. Patterns of antagonistic superiority among these strains form a highly linear dominance hierarchy. At least some competition pairs construct chimeric, rather than segregated, fruiting bodies. The cooperative prokaryote M. xanthus has diverged into a large number of distinct social types that cooperate with clone-mates but exhibit intense antagonism toward distinct social types of the same species. Most lengthy migration events in nature may thus result in strong antagonism between migratory and resident populations, and this antagonism may have large effects on local

  6. The gifts of silence and solitude.

    Science.gov (United States)

    Schmidt Bunkers, Sandra

    2008-01-01

    In this column the author describes the importance of finding silence and solitude amid the noise and technology present today in the teaching-learning academy. Three gifts of silence and solitude are identified: the gift of comforting aloneness, the gift of vision for new horizons, and the gift of a sense of freedom. A humanbecoming perspective is used to explore the implications of these gifts. This column introduces a column by Diana Vander Woude describing her teaching-learning experience in leadership focusing on silence and solitude. PMID:18096981

  7. Titration and hysteresis in epigenetic chromatin silencing

    International Nuclear Information System (INIS)

    Epigenetic mechanisms of silencing via heritable chromatin modifications play a major role in gene regulation and cell fate specification. We consider a model of epigenetic chromatin silencing in budding yeast and study the bifurcation diagram and characterize the bistable and the monostable regimes. The main focus of this paper is to examine how the perturbations altering the activity of histone modifying enzymes affect the epigenetic states. We analyze the implications of having the total number of silencing proteins, given by the sum of proteins bound to the nucleosomes and the ones available in the ambient, to be constant. This constraint couples different regions of chromatin through the shared reservoir of ambient silencing proteins. We show that the response of the system to perturbations depends dramatically on the titration effect caused by the above constraint. In particular, for a certain range of overall abundance of silencing proteins, the hysteresis loop changes qualitatively with certain jump replaced by continuous merger of different states. In addition, we find a nonmonotonic dependence of gene expression on the rate of histone deacetylation activity of Sir2. We discuss how these qualitative predictions of our model could be compared with experimental studies of the yeast system under anti-silencing drugs. (paper)

  8. The evolution of reduced antagonism--A role for host-parasite coevolution.

    Science.gov (United States)

    Gibson, A K; Stoy, K S; Gelarden, I A; Penley, M J; Lively, C M; Morran, L T

    2015-11-01

    Why do some host-parasite interactions become less antagonistic over evolutionary time? Vertical transmission can select for reduced antagonism. Vertical transmission also promotes coevolution between hosts and parasites. Therefore, we hypothesized that coevolution itself may underlie transitions to reduced antagonism. To test the coevolution hypothesis, we selected for reduced antagonism between the host Caenorhabditis elegans and its parasite Serratia marcescens. This parasite is horizontally transmitted, which allowed us to study coevolution independently of vertical transmission. After 20 generations, we observed a response to selection when coevolution was possible: reduced antagonism evolved in the copassaged treatment. Reduced antagonism, however, did not evolve when hosts or parasites were independently selected without coevolution. In addition, we found strong local adaptation for reduced antagonism between replicate host/parasite lines in the copassaged treatment. Taken together, these results strongly suggest that coevolution was critical to the rapid evolution of reduced antagonism.

  9. Structural basis for simvastatin competitive antagonism of complement receptor 3

    DEFF Research Database (Denmark)

    Jensen, Maria Risager; Bajic, Goran; Zhang, Xianwei;

    2016-01-01

    The complement system is an important part of the innate immune response to infection, but may also cause severe complications during inflammation. Small molecule antagonists to complement receptor (CR)3 have been widely sought, but a structural basis for their mode of action is not available. We...... report here on the structure of the human CR3 ligand-binding I domain in complex with simvastatin. Simvastatin targets the metal ion-dependent adhesion site of the open, ligand-binding conformation of the CR3 I domain by direct contact with the chelated Mg2+ ion. Simvastatin antagonizes I domain binding...... to the complement fragments iC3b and C3d, but not to intercellular adhesion molecule-1. By virtue of the I domain's wide distribution in binding kinetics to ligands, it was possible to identify ligand binding kinetics as discriminator for simvastatin antagonism. In static cellular experiments, 15-25 μM simvastatin...

  10. CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Po-Yin Chu

    Full Text Available Heart failure (HF is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice or type II diabetes (Israeli Sand-rats and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

  11. The Hedgehog inhibitor cyclopamine antagonizes chemoresistance of breast cancer cells

    OpenAIRE

    Chai F; Zhou J; Chen C; Xie S; Chen X.; Su P; Shi J

    2013-01-01

    Feng Chai,1 Jiangang Zhou,1 Cheng Chen,1 Song Xie,2 Xiao Chen,1 Ping Su,3 Jun Shi3 1Oncology Department, 2General Surgery Department, 3Hematology Department, Zhejiang Xiaoshan Hospital, Hangzhou, People's Republic of China Abstract: Chemoresistance of cancer cells has been a severe problem in multiple types of cancers. One possibility is to combine different drugs with chemotherapy for improved efficacy. Cyclopamine blocks Hedgehog signaling by antagonizing Smo function, which induce...

  12. Epigenetic chromatin silencing: bistability and front propagation

    Science.gov (United States)

    Sedighi, Mohammad; Sengupta, Anirvan M.

    2007-12-01

    The role of post-translational modification of histones in eukaryotic gene regulation is well recognized. Epigenetic silencing of genes via heritable chromatin modifications plays a major role in cell fate specification in higher organisms. We formulate a coarse-grained model of chromatin silencing in yeast and study the conditions under which the system becomes bistable, allowing for different epigenetic states. We also study the dynamics of the boundary between the two locally stable states of chromatin: silenced and unsilenced. The model could be of use in guiding the discussion on chromatin silencing in general. In the context of silencing in budding yeast, it helps us understand the phenotype of various mutants, some of which may be non-trivial to see without the help of a mathematical model. One such example is a mutation that reduces the rate of background acetylation of particular histone side chains that competes with the deacetylation by Sir2p. The resulting negative feedback due to a Sir protein depletion effect gives rise to interesting counter-intuitive consequences. Our mathematical analysis brings forth the different dynamical behaviors possible within the same molecular model and guides the formulation of more refined hypotheses that could be addressed experimentally.

  13. Active compressor engine silencer reduces exhaust noise

    International Nuclear Information System (INIS)

    An active industrial silencer on a compressor engine at a Tenneco Gas station has reduced low-frequency 'rumbling' noise by 8 dB during trials while lowering backpressure about 90$. This 8 dB reduction of the piston firing frequency corresponds to a more than 80% decrease in emitted acoustic power. The silencing unit, installed on one of six engines at the station near Eden, N.Y., continues in operation. Based on the results, the manufacturer is identifying additional compressor sites for further tests. This paper reviews this project

  14. Antagonism of some aquatic hyphomycetes against plant pathogenic fungi.

    Science.gov (United States)

    Sati, S C; Arya, P

    2010-01-01

    The antagonistic activity of five aquatic hyphomycetes, viz., Heliscus lugdunensis, Tetrachaetum elegans, Tetracladium breve, T. marchalianum, and T. nainitalense, against seven plant pathogenic fungi was studied using a dual culture technique. Inhibitory activity of tested aquatic hyphomycetes was determined by measuring the radial growth of plant pathogenic fungi on dual culture plates. Tetrachaetum elegans showed antagonistic activity against Colletotrichum falcatum, Fusarium oxysporum, Pyricularia oryzae, Sclerotium sclerotiorum, and Tilletia indica. Heliscus lugdunensis showed antagonism against only two plant pathogenic fungi, Rhizoctonia solani and Colletotrichum falcatum. Tetracladium breve, T. marchalianum, and T. nainitalense showed no response towards tested plant pathogenic fungi. PMID:20454756

  15. Antagonism of Some Aquatic Hyphomycetes against Plant Pathogenic Fungi

    Directory of Open Access Journals (Sweden)

    S. C. Sati

    2010-01-01

    Full Text Available The antagonistic activity of five aquatic hyphomycetes, viz., Heliscus lugdunensis, Tetrachaetum elegans, Tetracladium breve, T. marchalianum, and T. nainitalense, against seven plant pathogenic fungi was studied using a dual culture technique. Inhibitory activity of tested aquatic hyphomycetes was determined by measuring the radial growth of plant pathogenic fungi on dual culture plates. Tetrachaetum elegans showed antagonistic activity against Colletotrichum falcatum, Fusarium oxysporum, Pyricularia oryzae, Sclerotium sclerotiorum, and Tilletia indicaHeliscus lugdunensis showed antagonism against only two plant pathogenic fungi, Rhizoctonia solani and Colletotrichum falcatum.Tetracladium breve, T. marchalianum, and T. nainitalense showed no response towards tested plant pathogenic fungi.

  16. Antagonism of Type I Interferon Responses by New World Hantaviruses▿

    OpenAIRE

    Levine, Jessica R.; Prescott, Joseph; Kyle S. Brown; Best, Sonja M.; Ebihara, Hideki; Feldmann, Heinz

    2010-01-01

    Evasion of interferon (IFN)-mediated antiviral signaling is a common defense strategy for pathogenic RNA viruses. To date, research on IFN antagonism by hantaviruses is limited and has focused on only a subset of the numerous recognized hantavirus species. The host IFN response has two phases, an initiation phase, resulting in the induction of alpha/beta IFN (IFN-α/β), and an amplification phase, whereby IFN-α/β signals through the Jak/STAT pathway, resulting in the establishment of the cellu...

  17. Antagonism, social critique and the ‘violent reverie’

    OpenAIRE

    Hook, Derek

    2014-01-01

    This paper opens up a series of windows on racialised life in past and present South Africa as a way arguing for the value of antagonism as a mode of critical enquiry. Sampling a cross-section of recent writing on South African race politics, the paper calls attention both to strident critiques of white privilege, and to concerns over allegedly anti-white populism. Chabani Manganyi’s notion of the violent reverie is used to argue that such oppositional critique affords a crucial expressive mo...

  18. The Analysis of Silence in Conflict Talk with Face Theory

    Institute of Scientific and Technical Information of China (English)

    罗丹

    2016-01-01

    Silence and noisy speech can be functionally equivalent in the conflict. Sometimes the more serious the problem is, the more likely that conversationalists will use silence in the utterance because silence stops conflict evolving into violence. In the context of potentially explosive arguments, pauses or silences prevent the conflict from exploding and destroying the possibility of continuing the relationship. Thus the participant’s face will be saved.

  19. Mainstream Television, Adolescent Homosexuality, and Significant Silence.

    Science.gov (United States)

    Kielwasser, Alfred P.; Wolf, Michelle A.

    1992-01-01

    Argues that the symbolic annihilation of gay and lesbian youth exhibited by network television contributes to a dysfunctional isolation supported by the mutually reinforcing invisibility of homosexual adolescents on television and in the real world. Suggests that the spiral of silence also partially accounts for the inefficacy of oppositional…

  20. Veiled Word(s) – Sacred Silence

    DEFF Research Database (Denmark)

    Isar, Nicoletta

    2014-01-01

    or secret prayer, and divine silence, which are at the very centre of the Byzantine altar. The main focus is to investigate the liminal nature of the Mystery, manifested through concealing-revealing devices, which are thresholds in the liturgical participation of the Byzantine subject. Fear and secrecy...

  1. An Empirical Study on English Majors’Silence in Class

    Institute of Scientific and Technical Information of China (English)

    Zhao Lingzhi

    2014-01-01

    This paper aims to investigate the causes of English majors' silence in class and whether task-based approach can reduce silence by conducting an empirical study.The results indicates that students' self-esteem,motivation,personality and teachers' authority are the main causes of students' silence in class.

  2. The Power of Silence in To the Lighthouse

    Institute of Scientific and Technical Information of China (English)

    王艳

    2013-01-01

    Traditionally, silence is regarded as an absence, inaction, emptiness, or inferiority, but it figures in Woolf ’s novels as a presence, power, creativity, and superiority, and infused with a new psychic and narrative life. The present paper will examine Woolf’s expression of silence in her masterpiece To the Lighthouse to reveal the power of silence.

  3. An Empirical Study on English Majors’ Silence in Class

    Institute of Scientific and Technical Information of China (English)

    Zhao; Lingzhi

    2014-01-01

    This paper aims to investigate the causes of English majors’silence in class and whether task-based approach can reduce silence by conducting an empirical study.The results indicates that students’self-esteem,motivation,personality and teachers’authority are the main causes of students’silence in class.

  4. The Differences of Silence between Chinese and American Culture

    Institute of Scientific and Technical Information of China (English)

    巩飞

    2015-01-01

    Language is an important means of human communication; and silence can also convey a wealth of information.This paper will interpret the different definitions of silence phenomena between China and America and two different attitudes and representations of silence.It will help us to improve the effectiveness of communication.

  5. Is our knowledge of voice and silence in organizations growing?

    DEFF Research Database (Denmark)

    Knoll, Michael; Wegge, Jürgen; Unterrainer, Christine;

    2016-01-01

    integrative approach to the nature of silence and voice and their antecedents and consequences. These opportunities include a multi-level model specifying elements and processes leading to individual and collective voice and silence, approaches to voice and silence that have received little attention...

  6. Unpacking the Unspoken: Silence in Collective Memory and Forgetting

    Science.gov (United States)

    Vinitzky-Seroussi, Vered; Teeger, Chana

    2010-01-01

    Collective memory quite naturally brings to mind notions of mnemonic speech and representation. In this article, however, we propose that collective silences be thought of as a rich and promising arena through which to understand how groups deal with their collective pasts. In so doing, we explore two types of silence: overt silence and covert…

  7. The Sound of Silence: The Case of Virtual Team Organising

    Science.gov (United States)

    Panteli, N.; Fineman, S.

    2005-01-01

    In this paper we discuss the role of silence within a virtual organising context. The paper raises issues related to the construction of silence in the virtual team context and the implications it has on team interactions. By drawing upon existing studies on virtual teams, we argue that members' silence may not always have negative effects on team…

  8. Detailed characterization of the posttranscriptional gene-silencing-related small RNA in a GUS gene-silenced tobacco

    NARCIS (Netherlands)

    Hutvágner, G.; Mlynarova, L.; Nap, J.P.H.

    2000-01-01

    Posttranscriptional gene-silencing phenomena such as cosuppression and RNA interference are associated with the occurrence of small, about 21-23 nt short RNA species homologous to the silenced gene. We here show that the small RNA present in silenced transgenic plants can easily be detected in total

  9. Silence:An Effective Resistance in"No Name Woman"

    Institute of Scientific and Technical Information of China (English)

    戴淑琴

    2016-01-01

    "No Name Woman", written by Maxine Hong Kingston, depicts different life of Chinese or Chinese American women. They go through different life experiences, but their life experiences reflect the same attitude toward life that is silence. Is si-lence effective or not? By analyzing the textual contents, life experience of the aunt combining with contemporary social envi-ronment, the paper argues that silence is an effective resistance against patriarchal system. It illuminates the ways that resistance not only relies on violence, but also on silence and sometimes silence is more powerful than violence.

  10. Destructive Role of Employee Silence in Organizational Success

    Directory of Open Access Journals (Sweden)

    Malikeh Beheshtifar

    2012-11-01

    Full Text Available Employees are regarded as major sources of change, creativity, learning, and innovation, which are critical factors to the success of organizations. However, many employees choose not to voice their opinions and concerns about matters in their organizations. Silence can convey approval and sharing or disfavor and opposition, thus becoming a pressure mechanism for both individuals and organizations. Through silence, organizational members suppress concerns about difficult or troubling personal as well as organizational issues. Moreover, there are three types of employee silence as Acquiescent Silence, Defensive Silence, and Pro-social Silence. Fear, embarrassment, narrow conceptions of ethical responsibility, implicated friends, lack of opportunity for voice, and lack of organizational political skills are factors to cause silence. Employee silence has many effects on the employees themselves. Indifferent employees, often products of ignored employee silence, tend to feel like cogs at machinery factories, developing the attitude “to get along, go along”. Indifferent employees cause the organization to lose money and function poorly. If employee silence does occur, communication suffers and as a result harms the overall functioning of the organization. However, it is not easy to break silence climate of employees and their managers. Meanwhile, it is suggested to regulate some rules for supporting the employees' attitudes, to make decisions about the work groups of the organizations and to establish some programs in order to improve the human resource management for training skills of decision – making.

  11. Elucidating MOM1-mediated gene silencing

    OpenAIRE

    Smathajitt, Chotika

    2007-01-01

    Chez Arabidopsis, la protéine MOM1 (Morpheus' Molecule 1) est impliquée dans le silencing épigénétique des gènes. La mutante "mom1" ne présente aucun changement de méthylation de l'ADN, de modifications des histones ou de l'architecture nucléaire. Ces caractéristiques différencient nettement MOM1 des autres régulateurs épigénétiques connus. Durant ma thèse, j'ai utilisé deux approches afin d'identifier des composants additionnels participant au silencing dirigé par MOM1. La première approche ...

  12. Silencing Cinema. Film Censorship around the World

    OpenAIRE

    2013-01-01

    Why does oppression by censorship affect the film industry far more frequently than any other mass media? "Silencing Cinema" brings together the key issues and authors to examine instances of film censorship throughout the world. Including essays by some of today's leading film historians, the book offers groundbreaking historical research on film censorship in major film production countries, including the United States, the United Kingdom, Russia/Soviet Union, India, China, and Nigeria, amo...

  13. Experimental studies of a drumlike silencer.

    Science.gov (United States)

    Choy, Y S; Huang, Lixi

    2002-11-01

    The theoretical finding of the broadband performance of a reactive silencer is validated experimentally. The silencer consists of two highly stretched membranes lining part of the duct and backed by two long and shallow cavities. The test rig was built with a small square duct of 5 cm in dimension, and each cavity is 5 cm deep and 25 cm long. Two types of metal foils, stainless steel and copper, were used, and the lowest membrane-to-air mass ratio was 1.3. A transmission loss in excess of 10 dB was achieved over more than one octave band. For one configuration close to the optimal parameters, the predicted ratio of the frequency band limits is 2.47, while the experiment gave 2.35. Three spectral peaks were found in the stopband, as predicted, but the peaks were broader than prediction, indicating the presence of significant sound energy dissipation mechanisms. Comparison with theoretical simulation shows that the cavity damping dominates over membrane friction. Tests using heavier membranes and membrane with different levels of tension also agree with predictions. Issues of practical implementation of the concept as a flow-through silencer are also addressed.

  14. Analysis and design of pod silencers

    Science.gov (United States)

    Munjal, M. L.

    2003-05-01

    Parallel baffle mufflers or split silencers are used extensively in heating, ventilation and air conditioning systems for increased attenuation of noise within a short or given length. Acoustic analysis of rectangular parallel baffle mufflers runs on the same lines as that of a rectangular duct lined on two sides. This simplification would not hold for circular configurations. Often, a cylindrical pod is inserted into a circular lined duct to increase its attenuation (or transmission loss), thereby making the flow passage annular and providing an additional absorptive layer on the inner side of this annular passage. This configuration, called a pod silencer, is analyzed here for the four-pole parameters as well as transmission loss, making use of the bulk reaction model. The effect of thin protective film or a highly perforated metallic plate is duly incorporated by means of a grazing-flow impedance. Use of appropriate boundary conditions leads to a set of linear homogeneous equations which in turn lead to a transcendental frequency equation in the unknown complex axial wave number. This is solved by means of the Newton-Raphson method, and the axial wave number is then used in the expressions for transmission loss as well as the transfer matrix parameters. Finally, results of a parametric study are reported to help the designer in optimization of a pod silencer configuration within a given overall size for minimal cost.

  15. Therapeutic potential of endothelin receptor antagonism in kidney disease.

    Science.gov (United States)

    Czopek, Alicja; Moorhouse, Rebecca; Webb, David J; Dhaun, Neeraj

    2016-03-01

    Our growing understanding of the role of the endothelin (ET) system in renal physiology and pathophysiology is from emerging studies of renal disease in animal models and humans. ET receptor antagonists reduce blood pressure and proteinuria in chronic kidney disease and cause regression of renal injury in animals. However, the therapeutic potential of ET receptor antagonism has not been fully explored and clinical studies have been largely limited to patients with diabetic nephropathy. There remains a need for more work in nondiabetic chronic kidney disease, end-stage renal disease (patients requiring maintenance dialysis and those with a functioning kidney transplant), ischemia reperfusion injury, and sickle cell disease. The current review summarizes the most recent advances in both preclinical and clinical studies of ET receptor antagonists in the field of kidney disease.

  16. Interferon Induction by RNA Viruses and Antagonism by Viral Pathogens

    Directory of Open Access Journals (Sweden)

    Yuchen Nan

    2014-12-01

    Full Text Available Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR. Host PRR for RNA viruses include Toll-like receptors (TLR and retinoic acid-inducible gene I (RIG-I like receptors (RLR. Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

  17. Structural Basis for Simvastatin Competitive Antagonism of Complement Receptor 3.

    Science.gov (United States)

    Jensen, Maria Risager; Bajic, Goran; Zhang, Xianwei; Laustsen, Anne Kjær; Koldsø, Heidi; Skeby, Katrine Kirkeby; Schiøtt, Birgit; Andersen, Gregers R; Vorup-Jensen, Thomas

    2016-08-12

    The complement system is an important part of the innate immune response to infection but may also cause severe complications during inflammation. Small molecule antagonists to complement receptor 3 (CR3) have been widely sought, but a structural basis for their mode of action is not available. We report here on the structure of the human CR3 ligand-binding I domain in complex with simvastatin. Simvastatin targets the metal ion-dependent adhesion site of the open, ligand-binding conformation of the CR3 I domain by direct contact with the chelated Mg(2+) ion. Simvastatin antagonizes I domain binding to the complement fragments iC3b and C3d but not to intercellular adhesion molecule-1. By virtue of the I domain's wide distribution in binding kinetics to ligands, it was possible to identify ligand binding kinetics as discriminator for simvastatin antagonism. In static cellular experiments, 15-25 μm simvastatin reduced adhesion by K562 cells expressing recombinant CR3 and by primary human monocytes, with an endogenous expression of this receptor. Application of force to adhering monocytes potentiated the effects of simvastatin where only a 50-100 nm concentration of the drug reduced the adhesion by 20-40% compared with untreated cells. The ability of simvastatin to target CR3 in its ligand binding-activated conformation is a novel mechanism to explain the known anti-inflammatory effects of this compound, in particular because this CR3 conformation is found in pro-inflammatory environments. Our report points to new designs of CR3 antagonists and opens new perspectives and identifies druggable receptors from characterization of the ligand binding kinetics in the presence of antagonists. PMID:27339893

  18. Analysis of Silences in“The Dumb Waiter”

    Institute of Scientific and Technical Information of China (English)

    张晓莉

    2013-01-01

    Harold Pinter is one of the famous absurdist play writer in England. His works and language are full of absurd color, which is the focus of critics. Silence is a trademark of Harold Pinter’s writing. He uses it to an exquisite manner that he forms his individual“Pinteresque”silence. Silences in his play appear many times and act as a natural barrier for true self. This paper will take Pinter’s early work“The Dumb Waiter”for example to analysis the wide usage of silences in the play. The paper tries to un-mask the truth under silences. And by exploring the two types of silences, we can see characters ’true emotion and intention un-derground.

  19. Organizational Silence in Universities as the Predictor of Organizational Culture

    OpenAIRE

    Erkan YAMAN; Kayhan RUÇLAR

    2014-01-01

    The aim of this study is to determine the relationship between the sense of organizational silence and the organizational culture the instructors perceived. In this study, the scale for determining organizational culture developed by İpek (1999) and the scale for measuring organizational silence developed by Çakıcı (2007) and adapted by Soycan (2010) are used. No remarkable difference was found in the academic staff's sense of organizational silence degree according to their genders and educa...

  20. Nitrite-Mediated Antagonism of Cyanide Inhibition of Cytochrome c Oxidase in Dopamine Neurons

    OpenAIRE

    Leavesley, Heather B.; Li, Li; Mukhopadhyay, Soma; Borowitz, Joseph L.; Isom, Gary E.

    2010-01-01

    Cyanide inhibits aerobic metabolism by binding to the binuclear heme center of cytochrome c oxidase (CcOX). Amyl nitrite and sodium nitrite (NaNO2) antagonize cyanide toxicity in part by oxidizing hemoglobin to methemoglobin (mHb), which then scavenges cyanide. mHb generation is thought to be a primary mechanism by which the NO2− ion antagonizes cyanide. On the other hand, NO2− can undergo biotransformation to generate nitric oxide (NO), which may then directly antagonize cyanide inhibition o...

  1. The Enamovirus P0 protein is a silencing suppressor which inhibits local and systemic RNA silencing through AGO1 degradation.

    Science.gov (United States)

    Fusaro, Adriana F; Correa, Regis L; Nakasugi, Kenlee; Jackson, Craig; Kawchuk, Lawrence; Vaslin, Maite F S; Waterhouse, Peter M

    2012-05-10

    The P0 protein of poleroviruses and P1 protein of sobemoviruses suppress the plant's RNA silencing machinery. Here we identified a silencing suppressor protein (SSP), P0(PE), in the Enamovirus Pea enation mosaic virus-1 (PEMV-1) and showed that it and the P0s of poleroviruses Potato leaf roll virus and Cereal yellow dwarf virus have strong local and systemic SSP activity, while the P1 of Sobemovirus Southern bean mosaic virus supresses systemic silencing. The nuclear localized P0(PE) has no discernable sequence conservation with known SSPs, but proved to be a strong suppressor of local silencing and a moderate suppressor of systemic silencing. Like the P0s from poleroviruses, P0(PE) destabilizes AGO1 and this action is mediated by an F-box-like domain. Therefore, despite the lack of any sequence similarity, the poleroviral and enamoviral SSPs have a conserved mode of action upon the RNA silencing machinery. PMID:22361475

  2. The Enamovirus P0 protein is a silencing suppressor which inhibits local and systemic RNA silencing through AGO1 degradation

    International Nuclear Information System (INIS)

    The P0 protein of poleroviruses and P1 protein of sobemoviruses suppress the plant's RNA silencing machinery. Here we identified a silencing suppressor protein (SSP), P0PE, in the Enamovirus Pea enation mosaic virus-1 (PEMV-1) and showed that it and the P0s of poleroviruses Potato leaf roll virus and Cereal yellow dwarf virus have strong local and systemic SSP activity, while the P1 of Sobemovirus Southern bean mosaic virus supresses systemic silencing. The nuclear localized P0PE has no discernable sequence conservation with known SSPs, but proved to be a strong suppressor of local silencing and a moderate suppressor of systemic silencing. Like the P0s from poleroviruses, P0PE destabilizes AGO1 and this action is mediated by an F-box-like domain. Therefore, despite the lack of any sequence similarity, the poleroviral and enamoviral SSPs have a conserved mode of action upon the RNA silencing machinery.

  3. Heteronormativity and Silenced Sexualities at Work

    OpenAIRE

    Jolanta Reingardė

    2010-01-01

    The paper focuses on workplace as a space in which the normative versions of heterosexuality are produced. Facing the everyday reality of the closet, the majority of homosexual employees constructs and negotiates their silenced sexualities at work. The study is based on 30 in-depth interviews with Lithuanian gays and lesbians carried out within the framework of the EQUAL project “Open and Safe at Work.” The paper discusses how homosexuals confront heteronormativity at work and how it shapes t...

  4. A modular plasmid assembly kit for multigene expression, gene silencing and silencing rescue in plants.

    Directory of Open Access Journals (Sweden)

    Andreas Binder

    Full Text Available The Golden Gate (GG modular assembly approach offers a standardized, inexpensive and reliable way to ligate multiple DNA fragments in a pre-defined order in a single-tube reaction. We developed a GG based toolkit for the flexible construction of binary plasmids for transgene expression in plants. Starting from a common set of modules, such as promoters, protein tags and transcribed regions of interest, synthetic genes are assembled, which can be further combined to multigene constructs. As an example, we created T-DNA constructs encoding multiple fluorescent proteins targeted to distinct cellular compartments (nucleus, cytosol, plastids and demonstrated simultaneous expression of all genes in Nicotiana benthamiana, Lotus japonicus and Arabidopsis thaliana. We assembled an RNA interference (RNAi module for the construction of intron-spliced hairpin RNA constructs and demonstrated silencing of GFP in N. benthamiana. By combination of the silencing construct together with a codon adapted rescue construct into one vector, our system facilitates genetic complementation and thus confirmation of the causative gene responsible for a given RNAi phenotype. As proof of principle, we silenced a destabilized GFP gene (dGFP and restored GFP fluorescence by expression of a recoded version of dGFP, which was not targeted by the silencing construct.

  5. A Modular Plasmid Assembly Kit for Multigene Expression, Gene Silencing and Silencing Rescue in Plants

    Science.gov (United States)

    Binder, Andreas; Lambert, Jayne; Morbitzer, Robert; Popp, Claudia; Ott, Thomas; Lahaye, Thomas; Parniske, Martin

    2014-01-01

    The Golden Gate (GG) modular assembly approach offers a standardized, inexpensive and reliable way to ligate multiple DNA fragments in a pre-defined order in a single-tube reaction. We developed a GG based toolkit for the flexible construction of binary plasmids for transgene expression in plants. Starting from a common set of modules, such as promoters, protein tags and transcribed regions of interest, synthetic genes are assembled, which can be further combined to multigene constructs. As an example, we created T-DNA constructs encoding multiple fluorescent proteins targeted to distinct cellular compartments (nucleus, cytosol, plastids) and demonstrated simultaneous expression of all genes in Nicotiana benthamiana, Lotus japonicus and Arabidopsis thaliana. We assembled an RNA interference (RNAi) module for the construction of intron-spliced hairpin RNA constructs and demonstrated silencing of GFP in N. benthamiana. By combination of the silencing construct together with a codon adapted rescue construct into one vector, our system facilitates genetic complementation and thus confirmation of the causative gene responsible for a given RNAi phenotype. As proof of principle, we silenced a destabilized GFP gene (dGFP) and restored GFP fluorescence by expression of a recoded version of dGFP, which was not targeted by the silencing construct. PMID:24551083

  6. Organizational Silence in Universities as the Predictor of Organizational Culture

    Directory of Open Access Journals (Sweden)

    Erkan YAMAN

    2014-04-01

    Full Text Available The aim of this study is to determine the relationship between the sense of organizational silence and the organizational culture the instructors perceived. In this study, the scale for determining organizational culture developed by İpek (1999 and the scale for measuring organizational silence developed by Çakıcı (2007 and adapted by Soycan (2010 are used. No remarkable difference was found in the academic staff's sense of organizational silence degree according to their genders and educational backgrounds. It was seen that the instructors' sense of organizational silence had remarkable differences according to their age group, faculty, sense of administration type in their institutions, frequency of their face-to-face communication with their administrators and their thoughts of speaking clearly with their administrators. It was observed that research assistants had a significantly higher sense of organizational silence than the lecturers in the sense of ‘Lack of Experience'. It was seen that academicians who had 1-5 years of employment period had the highest sense of organizational silence while those who had 21 years or more employment period had the lowest sense of organizational silence in the sense of ‘Lack of Experience' of organizational silence. When the points that participant academicians got from organizational silence and organizational culture scales analyzed in the correlation table, it was found out that there was a remarkable relationship between the academicians' sense of organizational silence and sense of organizational culture. This relationship was a medium-level negative relationship between subdimensions of two scales. A medium-level negative relationship between the organizational silence (total and the organizational culture was also seen. Based on the findings, university administrators were proposed to create a participant culture in their institutions as well as to encourage instructors to speak clearly and

  7. Antagonism by theophylline of respiratory inhibition induced by adenosine.

    Science.gov (United States)

    Eldridge, F L; Millhorn, D E; Kiley, J P

    1985-11-01

    The effects on respiration of an analogue of adenosine, L-2-N6-(phenylisopropyl)adenosine (PIA), and of the methylxanthine, theophylline, were determined in 19 vagotomized glomectomized cats whose end-tidal PCO2 was kept constant by means of a servo-controlled ventilator. Integrated phrenic nerve activity was used to represent respiratory output. Our results show that PIA, whether given systemically or into the third cerebral ventricle, depressed respiration. Systemically administered theophylline stimulated respiration. Theophylline given intravenously, or into the third ventricle not only reversed the depressive effects of previously administered PIA but caused further increases of respiration above the control level. Prior systemic administration of theophylline blocked both respiratory and hypotensive effects of subsequently administered PIA. Effects of either agent on medullary extracellular fluid pH did not explain the results. We conclude that the adenosine analogue PIA, acts to inhibit neurons in the brain that are involved in the control of respiration and that its effects are blocked by theophylline. We suggest that adenosine acts as a tonic modulator of respiration and that theophylline stimulates breathing by competitive antagonism of adenosine at neuronal receptor sites. PMID:4066573

  8. Requirements within the Ebola Viral Glycoprotein for Tetherin Antagonism.

    Science.gov (United States)

    Vande Burgt, Nathan H; Kaletsky, Rachel L; Bates, Paul

    2015-10-01

    Tetherin is an interferon-induced, intrinsic cellular response factor that blocks release of numerous viruses, including Ebola virus, from infected cells. As with many viruses targeted by host factors, Ebola virus employs a tetherin antagonist, the viral glycoprotein (EboGP), to counteract restriction and promote virus release. Unlike other tetherin antagonists such as HIV-1 Vpu or KSHV K5, the features within EboGP needed to overcome tetherin are not well characterized. Here, we describe sequences within the EboGP ectodomain and membrane spanning domain (msd) as necessary to relieve tetherin restriction of viral particle budding. Fusing the EboGP msd to a normally secreted form of the glycoprotein effectively promotes Ebola virus particle release. Cellular protein or lipid anchors could not substitute for the EboGP msd. The requirement for the EboGP msd was not specific for filovirus budding, as similar results were seen with HIV particles. Furthermore trafficking of chimeric proteins to budding sites did not correlate with an ability to counter tetherin. Additionally, we find that a glycoprotein construct, which mimics the cathepsin-activated species by proteolytic removal of the EboGP glycan cap and mucin domains, is unable to counteract tetherin. Combining these results suggests an important role for the EboGP glycan cap and msd in tetherin antagonism. PMID:26516900

  9. Tachykinin receptors antagonism for asthma: a systematic review

    Directory of Open Access Journals (Sweden)

    Couto Nuno

    2011-08-01

    Full Text Available Abstract Background Tachykinins substance P, neurokinin A and neurokinin B seem to account for asthma pathophysiology by mediating neurogenic inflammation and several aspects of lung mechanics. These neuropeptides act mainly by their receptors NK1, NK2 and NK3, respectively which may be targets for new asthma therapy. Methods This review systematically examines randomized controlled trials evaluating the effect of tachykinins receptors antagonism on asthma. Symptoms, airway inflammation, lung function and airway inflammation were considered as outcomes. We searched the Cochrane Airways Group Specialized Register of Asthma Trials, Cochrane Database of Systematic Reviews, MEDLINE/PubMed and EMBASE. The search is as current as June 2010. Quality rating of included studies followed the Cochrane Collaboration and GRADE Profiler approaches. However, data were not pooled together due to different measures among the studies. Results Our systematic review showed the potential of NK receptor antagonist to decrease airway responsiveness and to improve lung function. However, effects on airway inflammation and asthma symptoms were poorly or not described. Conclusion The limited available evidence suggests that tachykinin receptors antagonists may decrease airway responsiveness and improve lung function in patients with asthma. Further large randomized trials are still required.

  10. Progress in Researches on the Effect of Acupuncture in Antagonizing Oxygen Stress

    Institute of Scientific and Technical Information of China (English)

    LI Zhong-ren; SHEN Mei-hong; PENG Yong-jun

    2005-01-01

    Oxidation and free radicals participate in the pathological process of multiple diseases in organisms, and acupuncture shows good effect in antagonizing oxygen stress (OS). This article reviews the effect of acupuncture in antagonizing oxygen stress and the mechanism of its antifree radical effect in various diseases. The authors hold that acupuncture not only has a chain-blocking effect, but also has preventive and repairing effects of anti-oxidation. And anti-OS action is one of the important mechanisms of acupuncture.

  11. Reflections on the Silencing the Self Scale and Its Origins

    Science.gov (United States)

    Jack, Dana Crowley

    2011-01-01

    In this article, the author reflects on the Silencing the Self Scale (STSS) and blends her personal and professional thoughts about self-silencing, gender, and depression. For her, the despair of depression deeply involves questions of value and meaning, culture and freedom. The STSS grew from listening to depressed women's voices. From them, the…

  12. Strategies underlying RNA silencing suppression by negative strand RNA viruses

    NARCIS (Netherlands)

    Hemmes, J.C.

    2007-01-01

    The research described in this thesis focused on the strategies of negative strand RNA viruses to counteract antiviral RNA silencing. In plants and insects, RNA silencing has been shown to act as a sequence specific antiviral defence mechanism that is characterised by the processing of double strand

  13. Multiple Interpretations of EFL Learners’ Silence in the Iranian Context

    Directory of Open Access Journals (Sweden)

    Reza Ghaffar Samar

    2013-11-01

    Full Text Available Attention to silence as part of the communicative discourse was first drawn in Sack’s (1974 paper, in which it was perceived as a linguistic and communicative form, and from the functional point of view as capable of expressing ideational, interpersonal, and textual functions. Awareness of multiple functions of silence including the referential, emotive, conative, phatic, poetic and metalanguage is of greater significance when it comes to language learning settings, where learners from a different cultural background from the target language are present to learn that language.  In such contexts, awareness of various functions of silence and correct interpretation of it is essential in teacher-student rapport. This paper aims to, first, provide an introduction to the multiple functions of silence in general and then to investigate these functions in EFL classes of Iran’s private language institutes. The researchers’ own teaching experience along with class observations and 2 phases of interview with teachers of those classes comprise the research data. Findings were indicative of teachers’ lack of awareness of diverse communicative functions of silence in class and that this awareness could be raised through the informal interview phases. This paper attests to the fact that not all learner’s silence should be interpreted negatively as lack of attention or knowledge. Teachers need to be aware of the salient meanings of silence in their EFL class and take an appropriate reactive step accordingly.Keywords: silence, Jakobson’s communicative model, culture, EFL, Iran

  14. Optimisation of acoustic silencer for the screw compressor system

    NARCIS (Netherlands)

    Swamy, M.; Lier, L.J. van; Smeulers, J.P.M.

    2014-01-01

    In one of the screw compressor system, designed silencer was not optimal. A great challenge was the large variation in operating conditions, especially the variation of the molecular weight of the gas. There was need to optimize the silencer. This paper describes the acoustic modelling tools to opti

  15. An Analysis of Heathcliff’s Silence in Wuthering Heights

    Institute of Scientific and Technical Information of China (English)

    潘琛

    2013-01-01

    Heathcliff is a highly controversial character in Emily Brontë’s canon Wuthering Heights. He is depicted as an incredi-ble conglomeration of enigmas and simplicity, aloofness and affinity, ferocity and vulnerability, inhumanity and heroicity, a man who appears more silent and preoccupied than talkative and carefree, inaudible and incalculable in both words and thoughts. The author of this paper considers that there is much left to be read and contemplate on in Heathcliff ’s silence and thus make a tempa-tive research into Heathcliff’s silence by discerning its manifestations and probing its causes, in order to resonate with the inner touch of this complicated soul and relate his silence with the spirit that Emily Brontë wished to deliver through Wuthering Heights. Heathcliff’s silence manifests as muteness, elusion and colloquial or physical violence. In his whole life, Heathcliff inter-mittently experiences the self-chosen silence and the forced silence. He chooses to be silence out of self-protection and the infe-riority complex;he considers silence as a token of masculinity. And the ruthless force from outside also compels him into a periph-eralized situation where he has to keep silent and struggles against the torture and torment alone.

  16. No-Big-Silence teeb klubituuri / Urmas Hännile

    Index Scriptorium Estoniae

    Hännile, Urmas

    2009-01-01

    Rockansamblist No-Big-Silence ja dark-popansamblist Sinine, nende kontsertttuurist mööda Eestimaad, tutvustamisel bändide uued albumid (No-Big-Silence "Starstealer" ja Sinine "Butterflies"), Pärnus on kontsert 24. oktoobril klubis Sugar

  17. Antiviral RNA silencing viral counter defense in plants

    NARCIS (Netherlands)

    Bucher, E.C.

    2006-01-01

    The research described in this thesis centres around the mechanism of RNA silencing in relation to virus-host interaction, an area of increasing importance. It shows how this recently disclosed mechanism can be used to produce virus-resistant plants. Based on the activity of the RNA silencing machin

  18. Silence: A Rhetorical Art for Resisting Discipline(s).

    Science.gov (United States)

    Glenn, Cheryl

    2002-01-01

    Argues that silence can be a specifically feminist rhetorical art, often one of resistance. Draws on two key rhetorical movements: the Anita Hill-Clarence Thomas hearings and the never-heard hearing of Lani Guinier. Explores the rhetorical dimensions of silence as a feminist position that can resist disciplinary pigeon-holing, embrace political…

  19. Effect of Synergism and Antagonism between Metals on Toxicity in Soils

    Institute of Scientific and Technical Information of China (English)

    ZHOUDE-ZHI; GUZONG-LIAN; 等

    1991-01-01

    Synergism and antagonism of cadmium(Cd),copper (Cu) and selenium (Se) to biological toxicities in red soil,yellow brown soil and black soil were evaluated by MICROTOX method.The relation between forms of the tested metals in soil and the synergism or antagonism between them was also studied.Results showed that owing to the difference of soil chemical properties,toxicity of these metals in soils was different.In red soil with acid reaction and low in cation exchange capacity,antagonism occurred significantly between metals when they coexisted at high concentrations,while synergism occurred only under low concentrations.It is indicated that in red soil,toxicity of metals affected by synergism or antagonism depends on concentration of the metals present.For yellow brown soil and black soil with larger cation exchange capacity and lower exchangeable aluminium(Al),no toxicity of metals was observed even if metals were added to soil in high concentrations.Synergism and antagonism between Cd,Cu and Se were controlled by the forms of metals present.The amount of water-soluble metals was the most important factor in determining synergism and antagonism. In this paper,comparisons of synergism and antagkonism between metals in soils and in water solutions were made.There occurred the synergism of metal toxicity in water solutions when the concentration of coexisting metals was high.This is just opposite to the case in soils.

  20. Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis

    Directory of Open Access Journals (Sweden)

    Zhang Junjie

    2011-02-01

    Full Text Available Abstract Background Autotaxin (ATX is a secreted glycoprotein with the lysophospholipase D (lysoPLD activity to convert lysophosphatidylcholine (LPC into lysophosphatidic acid (LPA, a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown. Results In the present study, we demonstrated that trichostatin A (TSA, a well-known HDAC inhibitor (HDACi, significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSA-induced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis. Conclusions We have demonstrated that ATX expression is repressed by HDAC3 and HDAC7 in cancer cells. During TSA treatment, ATX is induced due to the HDAC3 and HDAC7 inhibition and functionally antagonizes the TSA-induced apoptosis. These results reveal an internal HDACi-resistant mechanism in cancer cells, and suggest that the inhibition of ATX-LPA axis would be helpful to improve the efficacy of HDACi-based therapeutics against cancer.

  1. Screening and identification of virus-encoded RNA silencing suppressors.

    Science.gov (United States)

    Karjee, Sumona; Islam, Mohammad Nurul; Mukherjee, Sunil K

    2008-01-01

    RNA silencing, including RNA interference, is a novel method of gene regulation and one of the potent host-defense mechanisms against the viruses. In the course of evolution, the viruses have encoded proteins with the potential to suppress the host RNA silencing mechanism as a counterdefense strategy. The virus-encoded RNA silencing suppressors (RSSs) can serve as important biological tools to dissect the detailed RNA silencing pathways and also to evolve the antiviral strategies. Screening and identification of the RSSs are indeed of utmost significance in the field of plant biotechnology. We describe two Green Fluorescent Protein (GFP) reporter-based plant assay systems that rely on two different principles, namely reversal of silencing and enhancement of rolling circle replication (RCR) of geminiviral replicon. These proof-of-concept examples and assay systems could be used to screen various plant, animal, and insect viral ORFs for identification of the RSS activities.

  2. Chinanteco children’s silences in different classroom situations

    Directory of Open Access Journals (Sweden)

    Valeria Rebolledo Angulo

    2016-01-01

    Full Text Available This article analyzes, from an ethnographic perspective and a sociocultural framework, the construction of silences in the interaction between students and teachers in a multilingual classroom situation in an indigenous community in méxico. the analysis reveals how the silence of the chinanteco speaking children when asked to answer certain questions in class is not always due to their failure to understand spoken and written spanish that is used in class. their silences are responses taking different meanings in specific situations. the silence of the children can be a way of resisting, a way of hiding, and, sometimes, their voices are silenced.

  3. Viral counterdefense on RNA silencing : analysis of RNA silencing suppressors from arthropod-borne negative strand RNA plant viruses

    NARCIS (Netherlands)

    Schnettler, E.

    2010-01-01

    This thesis describes that RNA silencing suppressor (RSS) proteins encoded by negative-stranded RNA plant viruses are able to interfere with different RNA silencing pathways in a variety of organisms by interacting with double stranded (ds)RNA molecules. These RSS proteins are able to counteract the

  4. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    Science.gov (United States)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T; van der Horst, Geertje; Hemmer, Daniëlle M; Marijt, Koen A; Hwang, Ming S; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M; Meijer, Onno C; Culig, Zoran; van der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa. PMID:26483423

  5. GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells.

    Science.gov (United States)

    Tchasovnikarova, Iva A; Timms, Richard T; Matheson, Nicholas J; Wals, Kim; Antrobus, Robin; Göttgens, Berthold; Dougan, Gordon; Dawson, Mark A; Lehner, Paul J

    2015-06-26

    Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A nonlethal forward genetic screen in near-haploid KBM7 cells identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing.

  6. Antisense Gene Silencing: Therapy for Neurodegenerative Disorders?

    Directory of Open Access Journals (Sweden)

    Troels T. Nielsen

    2013-09-01

    Full Text Available Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders.

  7. Meiotic silencing by unpaired DNA: properties, regulation and suppression.

    Science.gov (United States)

    Shiu, Patrick K T; Metzenberg, Robert L

    2002-08-01

    In Neurospora, a gene not paired with a homolog in prophase I of meiosis generates a signal that transiently silences all sequences homologous to it by a process called meiotic silencing by unpaired DNA (MSUD). Thus a deletion mutation in a heterozygous cross is formally "ascus-dominant" because its unpaired wild-type partner silences itself. We describe in detail the isolation of a mutation, Sad-1(UV), that suppresses the dominance of various ascus-dominant mutations. Additional dominant, semidominant, and recessive Sad-1 alleles have been generated by RIP; the DNA of the dominant RIP alleles becomes methylated, but dim-2-dependent methylation is not necessary for silencing. The barrenness of homozygous Sad-1 crosses is not due to the failure to silence unpaired mating-type mat A-2 mat A-3 genes. Transcripts of sad-1(+) can be detected during the sexual phase in a homozygous wild-type cross, indicating that the gene is expressed even if all DNA can pair normally. Meiotic silencing is confined to the ascus in which DNA is unpaired, and silencing does not spread to neighboring asci in a fruiting body of mixed genetic constitution.

  8. The effect of eccentricity and spatiotemporal energy on motion silencing.

    Science.gov (United States)

    Choi, Lark Kwon; Bovik, Alan C; Cormack, Lawrence K

    2016-01-01

    The now well-known motion-silencing illusion has shown that salient changes among a group of objects' luminances, colors, shapes, or sizes may appear to cease when objects move rapidly (Suchow & Alvarez, 2011). It has been proposed that silencing derives from dot spacing that causes crowding, coherent changes in object color or size, and flicker frequencies combined with dot spacing (Choi, Bovik, & Cormack, 2014; Peirce, 2013; Turi & Burr, 2013). Motion silencing is a peripheral effect that does not occur near the point of fixation. To better understand the effect of eccentricity on motion silencing, we measured the amount of motion silencing as a function of eccentricity in human observers using traditional psychophysics. Fifteen observers reported whether dots in any of four concentric rings changed in luminance over a series of rotational velocities. The results in the human experiments showed that the threshold velocity for motion silencing almost linearly decreases as a function of log eccentricity. Further, we modeled the response of a population of simulated V1 neurons to our stimuli. We found strong matches between the threshold velocities on motion silencing observed in the human experiment and those seen in the energy model of Adelson and Bergen (1985). We suggest the plausible explanation that as eccentricity increases, the combined motion-flicker signal falls outside the narrow spatiotemporal frequency response regions of the modeled receptive fields, thereby reducing flicker visibility.

  9. Suppressors of RNA silencing encoded by tomato leaf curl betasatellites

    Indian Academy of Sciences (India)

    Richa Shukla; Sunita Dalal; V G Malathi

    2013-03-01

    Virus encoded RNA-silencing suppressors (RSSs) are the key components evolved by the viruses to counter RNA-silencing defense of plants. Whitefly-transmitted begomoviruses infecting tomato crop code for five different proteins, ORF AC4, ORF AC2 and ORF AV2 in DNA-A component, ORF BV1 in DNA-B and ORF C1 in satellite DNA which are predicted to function as silencing suppressors. In the present study suppressor function of ORF C1 of three betasatellites Tomato leaf curl Bangalore betasatellite ToLCBB-[IN:Hess:08], Cotton leaf curl Multan betasatellite CLCuMB–[IN:Sri:02] and Luffa leaf distortion betasatellite LuLDB-[IN:Lu:04] were examined. Agroinfiltration of GFP-silenced Nicotiana tabaccum cv. Xanthi with the cells expressing C1 protein resulted in reversal of silenced GFP expression. GFP-siRNA level was more than 50-fold lower compared to silenced plants in plants infiltrated with C1 gene from ToLCBB. However, in the case of 35S-C1 CLCuMB and 35S-C1 LuLDB construct, although GFP was expressed, siRNA level was not reduced, indicating that the step at which C1 interfere in RNA-silencing pathway is different.

  10. Transcriptional silencing of multiple genes in trophozoites of Entamoeba histolytica.

    Directory of Open Access Journals (Sweden)

    Rivka Bracha

    2006-05-01

    Full Text Available In a previous work we described the transcriptional silencing of the amoebapore A (AP-A gene (Ehap-a of Entamoeba histolytica strain HM-1:IMSS. The silencing occurred following transfection with a plasmid containing a 5' upstream region (473 bp of Ehap-a that included a truncated segment (140 bp of a short interspersed nuclear element (SINE1. Silencing remained in effect even after removal of the plasmid (clone G3. Neither short interfering RNA nor methylated DNA were detected, but the chromatin domain of Ehap-a in the gene-silenced trophozoites was modified. Two other similar genes (Ehap-b and one encoding a Saposin-like protein, SAPLIP 1 also became silenced. In the present work we demonstrate the silencing of a second gene of choice, one that encodes the light subunit of the Gal/GalNAc inhibitable lectin (Ehlgl1 and the other, the cysteine proteinase 5 (EhCP-5. This silencing occurred in G3 trophozoites transfected with a plasmid in which the 473 bp 5' upstream Ehap-a fragment was directly ligated to the second gene. Transcriptional silencing occurred in both the transgene and the chromosomal gene. SINE1 sequences were essential, as was a direct connection between the Ehap-a upstream region and the beginning of the open reading frame of the second gene. Gene silencing did not occur in strain HM-1:IMSS with any of these plasmid constructs. The trophozoites with two silenced genes were virulence-attenuated as were those of clone G3. In addition, trophozoites not expressing Lgl1 and AP-A proteins had a significantly reduced ability to cap the Gal/GalNAc-lectin to the uroid region when incubated with antibodies against the heavy (170 kDa subunit of the lectin. Lysates of trophozoites lacking cysteine proteinase 5 and AP-A proteins had 30% less cysteine proteinase activity than those of HM-1:IMSS strain or the G3 clone. Silencing of other genes in G3 amoebae could provide a model to study their various functions. In addition, double gene-silenced

  11. Two classes of short interfering RNA in RNA silencing

    OpenAIRE

    Hamilton, Andrew; Voinnet, Olivier; Chappell, Louise; Baulcombe, David

    2015-01-01

    RNA silencing is a eukaryotic genome defence system that involves processing of double-stranded RNA (dsRNA) into 21–26 nt, short interfering RNA (siRNA). The siRNA mediates suppression of genes corresponding to the dsRNA through targeted RNA degradation. In some plant systems there are additional silencing processes, involving systemic spread of silencing and RNA-directed methylation/transcriptional suppression of homologous genomic DNA. We show here that siRNAs produced in plants from a gree...

  12. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    Institute of Scientific and Technical Information of China (English)

    Yun-Liang Cui; Sheng Zhang; Zhao-Tao Tian; Zhao-Fen Lin; De-Chang Chen

    2016-01-01

    -O -cinnamoyl)-β-D-glucose,daucosterol linoleate,and rhein,at a low concentration,antagonized the MMP9-induced HUVEC monolayer permeability by promoting HUVEC proliferation and reducing extracellular VE-cadherin concentrations.

  13. The Effects of Vocational High School Teachers' Perceived Trust on Organizational Silence

    Science.gov (United States)

    Saglam, Aycan Çiçek

    2016-01-01

    The objective of this research is to reveal the effects of vocational school teachers' perceived organizational trust on organizational silence. For this purpose, at first teachers' perception on sub-dimensions of organizational silence and organizational trust, which are respectively "acquiescent silence," "defensive silence,"…

  14. Implications of Silence in Conversation within the Framework of Cooperative Principle

    Institute of Scientific and Technical Information of China (English)

    Chen Shiyao

    2014-01-01

    Silence is a common linguistic phenomenon which plays an important role in communication. This paper, taking a pragmatic perspective, analyzes silence in human communication and points out its pragmatic value. It indicates that silence is not a negative phenomenon with the Cooperative Principle and then deals with the implications of silence in conversation.

  15. Heteronormativity and Silenced Sexualities at Work

    Directory of Open Access Journals (Sweden)

    Jolanta Reingardė

    2010-01-01

    Full Text Available The paper focuses on workplace as a space in which the normative versions of heterosexuality are produced. Facing the everyday reality of the closet, the majority of homosexual employees constructs and negotiates their silenced sexualities at work. The study is based on 30 in-depth interviews with Lithuanian gays and lesbians carried out within the framework of the EQUAL project “Open and Safe at Work.” The paper discusses how homosexuals confront heteronormativity at work and how it shapes their sexual identity. How is heteronormativity reflected in their choices to stay in the closet or to come out? What are their coping strategies at work? The fear of open discrimination and violence leads to the invisibility of minority sexual orientation at work and the denial of sexuality as irrelevant to the social life. The internal division between sexual (private and social (public is evident in a number of ways. The suppression of the sexual is the most prevalent coping strategy in the heteronormative order.

  16. Improved design of PPRHs for gene silencing.

    Science.gov (United States)

    Rodríguez, Laura; Villalobos, Xenia; Solé, Anna; Lliberós, Carolina; Ciudad, Carlos J; Noé, Véronique

    2015-03-01

    Nowadays, the modulation of gene expression by nucleic acids has become a routine tool in biomedical research for target validation and it is also used to develop new therapeutic approaches. Recently, we developed the so-called polypurine reverse Hoogsteen hairpins (PPRHs) that show high stability and a low immunogenic profile and we demonstrated their efficacy both in vitro and in vivo. In this work, we explored different characteristics of PPRHs to improve their usage as a tool for gene silencing. We studied the role of PPRH length in the range from 20 to 30 nucleotides. We also proved their higher affinity of binding and efficacy on cell viability compared to nonmodified TFOs. To overcome possible off-target effects, we tested wild-type PPRHs, which proved to be capable of binding to their target sequence with more affinity, displaying a higher stability of binding and a higher effect in terms of cell viability. Moreover, we developed a brand new molecule called Wedge-PPRH with the ability to lock the ds-DNA into the displaced structure and proved its efficacy in prostate and breast cancer cell lines. PMID:25615267

  17. Oriana: the voice and the silences

    Directory of Open Access Journals (Sweden)

    Mercedes Rosúa

    2007-09-01

    Full Text Available Commentators did their best to bury the late Oriana Fallaci’s ideas and books written since the 11 S under tons of praises to her previous works, and under deep silence or global discrediting her denunciation of Islamic fundamentalism and of terrorist blackmail and all its forms of getting a grip on Europe. Obituary notices avoided carefully the analysis of facts and data brought forward by Oriana in her three last books: The rage and the pride. The power of the reason and Oriana Fallaci’s inter- view with herself. The Apocalypse. But the italian journalist, who past away on 15th Sep- tember 2006, denounced substantiated facts, true dangers and a real collusion of wes- tern sectors-venal, corrupt, fainthearted and ignorant-with the strategy of penetration and manipulation of public opinion of an islamic movement who is the enemy of democracies, Civil Rights, freedom and the western systems of open society.Key words: Oriana Fallaci, Islamic fundamentalism, Defence freedom, Denun- ciation fear, Europe ́s surrender, Terrorism, Western censorship. 

  18. Synthetic RNA silencing in bacteria - antimicrobial discovery and resistance breaking

    Directory of Open Access Journals (Sweden)

    James E.M. Stach

    2011-09-01

    Full Text Available The increasing incidence and prevalence of antibiotic resistance in bacteria threatens the antibiotic miracle. Conventional antimicrobial drug development has failed to replace the armamentarium needed to combat this problem, and novel solutions are urgently required. Here we review both natural and synthetic RNA silencing and its potential to provide new antibacterials through improved target selection, evaluation and screening. Furthermore, we focus on synthetic RNA silencers as a novel class of antibacterials and review their unique properties.

  19. Locus-specific ribosomal RNA gene silencing in nucleolar dominance.

    Directory of Open Access Journals (Sweden)

    Michelle S Lewis

    Full Text Available The silencing of one parental set of rRNA genes in a genetic hybrid is an epigenetic phenomenon known as nucleolar dominance. We showed previously that silencing is restricted to the nucleolus organizer regions (NORs, the loci where rRNA genes are tandemly arrayed, and does not spread to or from neighboring protein-coding genes. One hypothesis is that nucleolar dominance is the net result of hundreds of silencing events acting one rRNA gene at a time. A prediction of this hypothesis is that rRNA gene silencing should occur independent of chromosomal location. An alternative hypothesis is that the regulatory unit in nucleolar dominance is the NOR, rather than each individual rRNA gene, in which case NOR localization may be essential for rRNA gene silencing. To test these alternative hypotheses, we examined the fates of rRNA transgenes integrated at ectopic locations. The transgenes were accurately transcribed in all independent transgenic Arabidopsis thaliana lines tested, indicating that NOR localization is not required for rRNA gene expression. Upon crossing the transgenic A. thaliana lines as ovule parents with A. lyrata to form F1 hybrids, a new system for the study of nucleolar dominance, the endogenous rRNA genes located within the A. thaliana NORs are silenced. However, rRNA transgenes escaped silencing in multiple independent hybrids. Collectively, our data suggest that rRNA gene activation can occur in a gene-autonomous fashion, independent of chromosomal location, whereas rRNA gene silencing in nucleolar dominance is locus-dependent.

  20. Between Noise and Silence: Architecture since the 1970s

    OpenAIRE

    Alexandra Brown; Andrew Leach

    2012-01-01

    This essay considers noise in architectural discourse as it might lend form to issues hitherto tabled in rather different terms. We ask what noise offers this discussion or, perhaps better put, what seeing architectural debates in terms of distinctions between noise and silence, random and structured sound, silence as absence and pregnant void might add to disciplinary debates within architectural theory and criticism. By treating these acoustic values analogously rather than literally we wis...

  1. A nuclear-replicating viroid antagonizes infectivity and accumulation of a geminivirus by upregulating methylation-related genes and inducing hypermethylation of viral DNA

    Science.gov (United States)

    Torchetti, Enza Maria; Pegoraro, Mattia; Navarro, Beatriz; Catoni, Marco; Di Serio, Francesco; Noris, Emanuela

    2016-01-01

    DNA methylation and post-transcriptional gene silencing play critical roles in controlling infection of single-stranded (ss) DNA geminiviruses and ssRNA viroids, respectively, but both pathogens can counteract these host defense mechanisms and promote their infectivity. Moreover, a specific role of DNA methylation in viroid-host interactions is not yet confirmed. Here, using an experimental system where two nuclear-replicating agents, the geminivirus tomato yellow leaf curl Sardinia virus (TYLCSV) and potato spindle tuber viroid (PSTVd), co-infect their common host tomato, we observed that PSTVd severely interferes with TYLCSV infectivity and accumulation, most likely as a consequence of strong activation of host DNA methylation pathways. In fact, PSTVd alone or in co-infection with TYLCSV significantly upregulates the expression of key genes governing DNA methylation in plants. Using methylation-sensitive restriction and bisulfite conversion assays, we further showed that PSTVd infection promotes a strong hypermethylation of TYLCSV DNA, thus supporting a mechanistic link with the antagonism of the viroid on the virus in co-infected tomato plants. These results describe the interaction between two nuclear-replicating pathogens and show that they differentially interfere with DNA methylation pathways. PMID:27739453

  2. A Comparative Study on Performance Parameters of a Conventional Silencer versus Helmholtz Silencer Implemented On A 100cc Motorcycle

    Directory of Open Access Journals (Sweden)

    Saurabh Jadhav

    2014-06-01

    Full Text Available Automotive noise and pollution control are critical fields of study and research in recent years. Researchers all across the globe are focusing on making vehicles environmentally friendly by reducing sound and air pollution achieved through implementing various modern technologies. This paper concentrates on the study of noise and pollution performance of a 100cc motorbike on a custom fabricated Helmholtz silencer over a conventional silencer.

  3. A Comparative Study on Performance Parameters of a Conventional Silencer versus Helmholtz Silencer Implemented On A 100cc Motorcycle

    OpenAIRE

    Saurabh Jadhav; Apoorv Prem

    2014-01-01

    Automotive noise and pollution control are critical fields of study and research in recent years. Researchers all across the globe are focusing on making vehicles environmentally friendly by reducing sound and air pollution achieved through implementing various modern technologies. This paper concentrates on the study of noise and pollution performance of a 100cc motorbike on a custom fabricated Helmholtz silencer over a conventional silencer.

  4. The Enamovirus P0 protein is a silencing suppressor which inhibits local and systemic RNA silencing through AGO1 degradation

    Energy Technology Data Exchange (ETDEWEB)

    Fusaro, Adriana F. [University of Sydney, NSW 2006 (Australia); CSIRO Plant Industry, Canberra, P.O. Box 1600, ACT 2601 (Australia); Correa, Regis L. [CSIRO Plant Industry, Canberra, P.O. Box 1600, ACT 2601 (Australia); Depto. de Virologia, IMPPG, UFRJ, 21941-902 (Brazil); Nakasugi, Kenlee; Jackson, Craig [University of Sydney, NSW 2006 (Australia); Kawchuk, Lawrence [Research Centre, Agriculture and Agri-Food Canada, Lethbridge, AB T1J4B1 (Canada); Vaslin, Maite F.S. [Depto. de Virologia, IMPPG, UFRJ, 21941-902 (Brazil); Waterhouse, Peter M., E-mail: peter.waterhouse@sydney.edu.au [University of Sydney, NSW 2006 (Australia); CSIRO Plant Industry, Canberra, P.O. Box 1600, ACT 2601 (Australia)

    2012-05-10

    The P0 protein of poleroviruses and P1 protein of sobemoviruses suppress the plant's RNA silencing machinery. Here we identified a silencing suppressor protein (SSP), P0{sup PE}, in the Enamovirus Pea enation mosaic virus-1 (PEMV-1) and showed that it and the P0s of poleroviruses Potato leaf roll virus and Cereal yellow dwarf virus have strong local and systemic SSP activity, while the P1 of Sobemovirus Southern bean mosaic virus supresses systemic silencing. The nuclear localized P0{sup PE} has no discernable sequence conservation with known SSPs, but proved to be a strong suppressor of local silencing and a moderate suppressor of systemic silencing. Like the P0s from poleroviruses, P0{sup PE} destabilizes AGO1 and this action is mediated by an F-box-like domain. Therefore, despite the lack of any sequence similarity, the poleroviral and enamoviral SSPs have a conserved mode of action upon the RNA silencing machinery.

  5. A `Clicked' Tetrameric Hydroxamic Acid Glycopeptidomimetic Antagonizes Sugar-Lectin Interactions On The Cellular Level

    Science.gov (United States)

    Zhang, Hai-Lin; Zang, Yi; Xie, Juan; Li, Jia; Chen, Guo-Rong; He, Xiao-Peng; Tian, He

    2014-07-01

    A tetrameric N-acetyl galactosaminyl (GalNAc) peptidomimetic was constructed by N-acetylation of repeating proline-based hydroxamic acid units, followed by a convergent `click chemistry' coupling. This novel glycopeptidomimetic was determined to effectively antagonize the interaction between a transmembrane hepatic lectin and GalNAc on the cellular level.

  6. FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

    DEFF Research Database (Denmark)

    Jensen, Kim Steen; Binderup, Tina; Jensen, Klaus Thorleif;

    2011-01-01

    cell survival in hypoxia. FoxO3A is recruited to the promoters of nuclear-encoded mitochondrial genes where it directly antagonizes c-Myc function via a mechanism that does not require binding to the consensus FoxO recognition element. Furthermore, we show that FoxO3A is activated in human hypoxic...

  7. THE FUNGICIDE PROCHLORAZ: IN VITRO ANDROGEN ANTAGONISM, PARTURITION DELAYS, AND MALE REPRODUCTIVE MALFORMATIONS IN RATS

    Science.gov (United States)

    The Fungicide Prochloraz: In vitro Androgen Antagonism, Parturition Delays, and Male Reproductive Malformations in Rats.Nigel C. Noriega, Joseph Ostby, Christy Lambright, Vickie S. Wilson, and L. Earl Gray Jr., noriega.nigel@epa.govUS EPAProchloraz (PZ) is an imid...

  8. Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo

    DEFF Research Database (Denmark)

    Johansen, H K; Jensen, T G; Dessau, Ram;

    2000-01-01

    The combination of beta-lactam antibiotics and macrolides is often recommended for the initial empirical treatment of acute pneumonia in order to obtain activity against the most important pathogens. Theoretically, this combination may be inexpedient, as the bacteriostatic agent may antagonize th...

  9. On the robustness of SAC silencing in closed mitosis

    Science.gov (United States)

    Ruth, Donovan; Liu, Jian

    Mitosis equally partitions sister chromatids to two daughter cells. This is achieved by properly attaching these chromatids via their kinetochores to microtubules that emanate from the spindle poles. Once the last kinetochore is properly attached, the spindle microtubules pull the sister chromatids apart. Due to the dynamic nature of microtubules, however, kinetochore-microtubule attachment often goes wrong. When this erroneous attachment occurs, it locally activates an ensemble of proteins, called the spindle assembly checkpoint proteins (SAC), which halts the mitotic progression until all the kinetochores are properly attached by spindle microtubules. The timing of SAC silencing thus determines the fidelity of chromosome segregation. We previously established a spatiotemporal model that addresses the robustness of SAC silencing in open mitosis for the first time. Here, we focus on closed mitosis by examining yeast mitosis as a model system. Though much experimental work has been done to study the SAC in cells undergoing closed mitosis, the processes responsible are not well understood. We leverage and extend our previous model to study SAC silencing mechanism in closed mitosis. We show that a robust signal of the SAC protein accumulation at the spindle pole body can be achieved. This signal is a nonlinear increasing function of number of kinetochore-microtubule attachments, and can thus serve as a robust trigger to time the SAC silencing. Together, our mechanism provides a unified framework across species that ensures robust SAC silencing and fidelity of chromosome segregation in mitosis. Intramural research program in NHLBI at NIH.

  10. Precedents and consequences of prosocial behaviors of voice and silence

    Directory of Open Access Journals (Sweden)

    Alicia Omar

    2015-09-01

    Full Text Available Prosocial behavior is that which that encourages solidarity and harmony in interpersonal relationships, and produce personal or collective benefits. Although early research on job prosociality was focused on the study of conventional behaviors such as help, courtesy and sportsmanship, the identification and operationalization of new dimensions is rapidly expanding this nomological network. Such is the case of prosocial voice and prosocial silence, recently introduced in the scientific literature. The aim of this study is to explore possible relationships between employee’s voice and employee’s silence, and their personality structure; and examine the role of interpersonal justice perceptions on such relationships. We worked with a sample of 316 employees- aged 37 years and holding a 4.2-year signority working at public and private companies in southern and central Rosario (Argentina. The subjects completed Colquitt’ Justice Organizational Scale, Eysenck Personality Questionnaire, and Van Dyne’s Prosocial Voice and Prosocial Silence Scales. Extraversion and neuroticism emerged as the strongest predictors of prosocial voice and prosocial silence, respectively. Interpersonal justice perceptions emerged as moderators of the ‘natural’ tendency of extraverted workers to engage in prosocial voice, and emotionally controlled workers to engage in prosocial silence. Such findings would indicate that the promotion of high levels of interpersonal justice on job contexts could help workers to engage in more prosocial behavior with positive effects for the organization. 

  11. Write Silence, Silence Writing. Notes on an Avant-Garde Poetics of Absence

    Directory of Open Access Journals (Sweden)

    Teresa Puche Gutiérrez

    2011-10-01

    Full Text Available Modernity has raised, among other controversies, an outspoken interest in establishing the coordinates through which the word, imperfect and dependent, sensitive, primary and impure form, can transform herself in content, thought, poetic essence. Since the dissolution of traditional metrical forms until the election of silence as a single solution, which would represent the possible more purified form, there is a process that is consolidated during that historic space-time we call avant-garde. Taking as a starting point the poetry of León Felipe, seeks an approach to the poetic purism whose more representative development occurred in the context of avant-garde of the early twentieth century.

  12. The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.

    Directory of Open Access Journals (Sweden)

    Xing-sheng Shu

    Full Text Available BACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5 nasopharyngeal, 44% (8/18 esophageal, 76% (13/17 gastric, 50% (2/4 cervical, and 25% (3/12 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP in multiple primary tumors, including 93% (43/46 nasopharyngeal, 58% (25/43 esophageal, 88% (37/42 gastric and 63% (29/46 hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines. CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.

  13. Essential role of Drosophila Hdacl in homeotic gene silencing

    Institute of Scientific and Technical Information of China (English)

    Yuh-LongChang; Yu-HueiPeng; I-ChingPan; Der-ShanSun; BalasKing; Der-HwaHuang

    2005-01-01

    Deacetylation of the N-terminal tails of core histones plays a crucial role in gene silencing. Rpd3 and Hdal represent two major types of genes encoding trichostatin A-sensitive histone deacetylases. Although they have been widely found, their cellular and developmental roles remain to be elucidated in metazoa. We show that Drosophila Hdacl, an Rpd3-type gene, interacts cooperatively with Polycomb group repressors in silencing the homeotic genes that are essential for axial patterning of body segments. The biochem-ical copurification and cytological colocalization of HDAC1 and Polycomb group repressors strongly suggest that HDAC1 is a component of the silencing complex for chromatin modification on specific regulatory regions of homeotic genes.

  14. Telomeric position effect--a third silencing mechanism in eukaryotes.

    Directory of Open Access Journals (Sweden)

    J Greg Doheny

    Full Text Available Eukaryotic chromosomes terminate in telomeres, complex nucleoprotein structures that are required for chromosome integrity that are implicated in cellular senescence and cancer. The chromatin at the telomere is unique with characteristics of both heterochromatin and euchromatin. The end of the chromosome is capped by a structure that protects the end and is required for maintaining proper chromosome length. Immediately proximal to the cap are the telomere associated satellite-like (TAS sequences. Genes inserted into the TAS sequences are silenced indicating the chromatin environment is incompatible with transcription. This silencing phenomenon is called telomeric position effect (TPE. Two other silencing mechanisms have been identified in eukaryotes, suppressors position effect variegation [Su(vars, greater than 30 members] and Polycomb group proteins (PcG, approximately 15 members. We tested a large number of each group for their ability to suppress TPE [Su(TPE]. Our results showed that only three Su(vars and only one PcG member are involved in TPE, suggesting silencing in the TAS sequences occurs via a novel silencing mechanism. Since, prior to this study, only five genes have been identified that are Su(TPEs, we conducted a candidate screen for Su(TPE in Drosophila by testing point mutations in, and deficiencies for, proteins involved in chromatin metabolism. Screening with point mutations identified seven new Su(TPEs and the deficiencies identified 19 regions of the Drosophila genome that harbor suppressor mutations. Chromatin immunoprecipitation experiments on a subset of the new Su(TPEs confirm they act directly on the gene inserted into the telomere. Since the Su(TPEs do not overlap significantly with either PcGs or Su(vars, and the candidates were selected because they are involved generally in chromatin metabolism and act at a wide variety of sites within the genome, we propose that the Su(TPE represent a third, widely used, silencing

  15. Identifizierung und Charakterisierung von Silencing Suppressoren in Arabidopsis

    OpenAIRE

    Thran, Moritz

    2013-01-01

    Post-transkriptionelles gene silencing (PTGS) kann ein limitierender Faktor für die Expression von Transgenen sein. Transgene mRNAs können von der RNA-DEPENDENT RNA POLYMERASE 6 (RDR6) erkannt werden, was die Synthese doppelsträngiger RNA (dsRNA) initiiert und die Akkumulation von small interfering RNAs (siRNAs) zur Folge hat. Diese vermitteln die sequenzspezifische endonukleolytische Spaltung einer Ziel-mRNA und verhindern somit deren Akkumulation. Für die Initiierung des Transgen Silencing ...

  16. Between Noise and Silence: Architecture since the 1970s

    Directory of Open Access Journals (Sweden)

    Alexandra Brown

    2012-11-01

    Full Text Available This essay considers noise in architectural discourse as it might lend form to issues hitherto tabled in rather different terms. We ask what noise offers this discussion or, perhaps better put, what seeing architectural debates in terms of distinctions between noise and silence, random and structured sound, silence as absence and pregnant void might add to disciplinary debates within architectural theory and criticism. By treating these acoustic values analogously rather than literally we wish to suggest that reading the late postmodern moment through this filter opens out new possibilities for a critical assessment of this period and its present-day legacies.

  17. The Voice of Silence in Communication-from cross-culture perspective

    Institute of Scientific and Technical Information of China (English)

    曹琪雯

    2014-01-01

    This paper makes a study of silence from cross-culture perspective and holds that silence is an indispensable compo-nent of human communication without which the proper decoding of the information would be impossible.

  18. The Research on the Silence Phenomena of Students in College English Classroom Teaching

    Institute of Scientific and Technical Information of China (English)

    杨六兰

    2015-01-01

    This paper analyzes the reasons that resulted in silence phenomena in college English classroom teaching,and gives some feasible suggestions to break the classroom silence in English classroom teaching.

  19. Identification of Pns6, a putative movement protein of RRSV, as a silencing suppressor

    Directory of Open Access Journals (Sweden)

    Lin Qiying

    2010-11-01

    Full Text Available Abstract RNA silencing is a potent antiviral response in plants. As a counterdefense, most plant and some animal viruses encode RNA silencing suppressors. In this study, we showed that Pns6, a putative movement protein of Rice ragged stunt virus (RRSV, exhibited silencing suppressor activity in coinfiltration assays with the reporter green fluorescent protein (GFP in transgenic Nicotiana benthamiana line 16c. Pns6 of RRSV suppressed local silencing induced by sense RNA but had no effect on that induced by dsRNA. Deletion of a region involved in RNA binding abolished the silencing suppressor activity of Pns6. Further, expression of Pns6 enhanced Potato virus × pathogenicity in N. benthamiana. Collectively, these results suggested that RRSV Pns6 functions as a virus suppressor of RNA silencing that targets an upstream step of the dsRNA formation in the RNA silencing pathway. This is the first silencing suppressor to be identified from the genus Oryzavirus.

  20. Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives.

    Science.gov (United States)

    Schepetkin, Igor A; Khlebnikov, Andrei I; Kirpotina, Liliya N; Quinn, Mark T

    2016-08-01

    Formyl peptide receptor 1 (FPR1) regulates a wide variety of neutrophil functional responses and plays an important role in inflammation and the pathogenesis of various diseases. To date, a variety of natural and synthetic molecules have been identified as FPR1 ligands. Here, we review current knowledge on natural products and natural product-inspired small molecules reported to antagonize and/or inhibit the FPR1-mediated responses. Based on this literature, additional screening of selected commercially available natural compounds for their ability to inhibit fMLF-induced Ca(2+) mobilization in human neutrophils and FPR1 transfected HL-60 cells, and pharmacophore modeling, natural products with potential as FPR1 antagonists are considered and discussed in this review. The identification and characterization of natural products that antagonize FPR1 activity may have potential for the development of novel therapeutics to limit or alter the outcome of inflammatory processes. PMID:26382576

  1. Bureaucratic Constructions of Sexual Diversity: "Sensitive", "Controversial" and Silencing

    Science.gov (United States)

    Ullman, Jacqueline; Ferfolja, Tania

    2015-01-01

    National research illustrates the high degree of discrimination that prevails against lesbian, gay, bisexual, transgender and queer (LGBTQ) students resulting in diminished educational outcomes, both academic and social. This phenomenon is influenced by the prevalence of whole-school silences around LGBTQ topics in many Australian schools. This…

  2. Disease-Causing Allele-Specific Silencing by RNA Interference

    Directory of Open Access Journals (Sweden)

    Hirohiko Hohjoh

    2013-04-01

    Full Text Available Small double-stranded RNAs (dsRNAs of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi. Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become a powerful reverse genetic tool for suppressing the expression of a gene of interest in mammals, including human, and its application has been expanding to various fields. Recent studies further suggest that synthetic siRNA duplexes have the potential for specifically inhibiting the expression of an allele of interest without suppressing the expression of other alleles, i.e., siRNA duplexes likely confer allele-specific silencing. Such gene silencing by RNAi is an advanced technique with very promising applications. In this review, I would like to discuss the potential utility of allele-specific silencing by RNAi as a therapeutic method for dominantly inherited diseases, and describe possible improvements in siRNA duplexes for enhancing their efficacy.

  3. Breaking Classroom Silences: A View from Linguistic Ethnography

    Science.gov (United States)

    Rampton, Ben; Charalambous, Constadina

    2016-01-01

    This paper addresses potentially problematic classroom episodes in which someone foregrounds a social division that is normally taken for granted. It illustrates the way in which linguistic ethnography can unpack the layered processes that collide in the breaking of silence, showing how linguistic form and practice, individual positioning, local…

  4. Breaking the Silence: Helping Battered Moms and Their Children.

    Science.gov (United States)

    Texas Child Care, 2000

    2000-01-01

    Discusses issues of domestic violence to help child caregivers care for children more effectively. Considers the causes of domestic violence and its impact on children and families, and offers resources for more information as well as suggestions for helping an abused person get help. Includes lists of "Do's and don'ts for breaking the silence"…

  5. Studies of the silencing of Baculovirus DNA binding protein

    NARCIS (Netherlands)

    Quadt, I.; Lent, van J.W.M.; Knebel-Morsdorf, D.

    2007-01-01

    Baculovirus DNA binding protein (DBP) binds preferentially single-stranded DNA in vitro and colocalizes with viral DNA replication sites. Here, its putative role as viral replication factor has been addressed by RNA interference. Silencing of DBP in Autographa californica multiple nucleopolyhedrovir

  6. The "motion silencing" illusion results from global motion and crowding.

    Science.gov (United States)

    Turi, Marco; Burr, David

    2013-04-18

    Suchow and Alvarez (2011) recently devised a striking illusion, where objects changing in color, luminance, size, or shape appear to stop changing when they move. They refer to the illusion as "motion silencing of awareness to visual change." Here we present evidence that the illusion results from two perceptual processes: global motion and crowding. We adapted Suchow and Alvarez's stimulus to three concentric rings of dots, a central ring of "target dots" flanked on either side by similarly moving flanker dots. Subjects had to identify in which of two presentations the target dots were continuously changing (sinusoidally) in size, as distinct from the other interval in which size was constant. The results show: (a) Motion silencing depends on target speed, with a threshold around 0.2 rotations per second (corresponding to about 10°/s linear motion). (b) Silencing depends on both target-flanker spacing and eccentricity, with critical spacing about half eccentricity, consistent with Bouma's law. (c) The critical spacing was independent of stimulus size, again consistent with Bouma's law. (d) Critical spacing depended strongly on contrast polarity. All results imply that the "motion silencing" illusion may result from crowding.

  7. Design curves for circular and annular duct silencers

    Science.gov (United States)

    Watson, Willie R.; Ramakrishnan, R.

    1989-01-01

    Conventional models of sound propagation between porous walls (Scott, 1946) are adapted in order to calculate design curves for the lined circular and annular-duct silencers used in HVAC systems. The derivation of the governing equations is outlined, and results for two typical cases are presented graphically. Good agreement with published experimental data is demonstrated.

  8. Targeted silencing of anthrax toxin receptors protects against anthrax toxins.

    Science.gov (United States)

    Arévalo, Maria T; Navarro, Ashley; Arico, Chenoa D; Li, Junwei; Alkhatib, Omar; Chen, Shan; Diaz-Arévalo, Diana; Zeng, Mingtao

    2014-05-30

    Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax.

  9. When to Shut Students Up: Civility, Silencing, and Free Speech

    Science.gov (United States)

    Callan, Eamonn

    2011-01-01

    Teachers sometimes shut students up for the sake of civility. My question is whether silencing for the sake of civility can be morally justified when a student derogates fellow students as members of some widely stigmatized group, and the offending speech is not for any further reason to be deplored, for example, as a personally targeted insult.…

  10. Viral RNA Silencing Suppression: The Enigma of Bunyavirus NSs Proteins

    Directory of Open Access Journals (Sweden)

    Marcio Hedil

    2016-07-01

    Full Text Available The Bunyaviridae is a family of arboviruses including both plant- and vertebrate-infecting representatives. The Tospovirus genus accommodates plant-infecting bunyaviruses, which not only replicate in their plant host, but also in their insect thrips vector during persistent propagative transmission. For this reason, they are generally assumed to encounter antiviral RNA silencing in plants and insects. Here we present an overview on how tospovirus nonstructural NSs protein counteracts antiviral RNA silencing in plants and what is known so far in insects. Like tospoviruses, members of the related vertebrate-infecting bunyaviruses classified in the genera Orthobunyavirus, Hantavirus and Phlebovirus also code for a NSs protein. However, for none of them RNA silencing suppressor activity has been unambiguously demonstrated in neither vertebrate host nor arthropod vector. The second part of this review will briefly describe the role of these NSs proteins in modulation of innate immune responses in mammals and elaborate on a hypothetical scenario to explain if and how NSs proteins from vertebrate-infecting bunyaviruses affect RNA silencing. If so, why this discovery has been hampered so far.

  11. Viral RNA Silencing Suppression: The Enigma of Bunyavirus NSs Proteins.

    Science.gov (United States)

    Hedil, Marcio; Kormelink, Richard

    2016-01-01

    The Bunyaviridae is a family of arboviruses including both plant- and vertebrate-infecting representatives. The Tospovirus genus accommodates plant-infecting bunyaviruses, which not only replicate in their plant host, but also in their insect thrips vector during persistent propagative transmission. For this reason, they are generally assumed to encounter antiviral RNA silencing in plants and insects. Here we present an overview on how tospovirus nonstructural NSs protein counteracts antiviral RNA silencing in plants and what is known so far in insects. Like tospoviruses, members of the related vertebrate-infecting bunyaviruses classified in the genera Orthobunyavirus, Hantavirus and Phlebovirus also code for a NSs protein. However, for none of them RNA silencing suppressor activity has been unambiguously demonstrated in neither vertebrate host nor arthropod vector. The second part of this review will briefly describe the role of these NSs proteins in modulation of innate immune responses in mammals and elaborate on a hypothetical scenario to explain if and how NSs proteins from vertebrate-infecting bunyaviruses affect RNA silencing. If so, why this discovery has been hampered so far. PMID:27455310

  12. Mobile gene silencing in Arabidopsis is regulated by hydrogen peroxide

    Directory of Open Access Journals (Sweden)

    Dacheng Liang

    2014-12-01

    Full Text Available In plants and nematodes, RNAi can spread from cells from which it is initiated to other cells in the organism. The underlying mechanism controlling the mobility of RNAi signals is not known, especially in the case of plants. A genetic screen designed to recover plants impaired in the movement but not the production or effectiveness of the RNAi signal identified RCI3, which encodes a hydrogen peroxide (H2O2-producing type III peroxidase, as a key regulator of silencing mobility in Arabidopsis thaliana. Silencing initiated in the roots of rci3 plants failed to spread into leaf tissue or floral tissue. Application of exogenous H2O2 reinstated the spread in rci3 plants and accelerated it in wild-type plants. The addition of catalase or MnO2, which breaks down H2O2, slowed the spread of silencing in wild-type plants. We propose that endogenous H2O2, under the control of peroxidases, regulates the spread of gene silencing by altering plasmodesmata permeability through remodelling of local cell wall structure, and may play a role in regulating systemic viral defence.

  13. Organizational Justice As a Predictor of Organizational Silence

    Science.gov (United States)

    Tan, Çetin

    2014-01-01

    In this study, relation between teachers' perception for organizational justice and their organizational silence was examined. Sample of this study consists of 300 teachers who work at elementary schools in Siirt. Relational Scanning model was utilized in performance of this study. In this study, Organizational Justice Scale and…

  14. Maternal Silences: Motherhood and Voluntary Childlessness in Contemporary Christianity

    Directory of Open Access Journals (Sweden)

    Dawn Llewellyn

    2016-06-01

    Full Text Available In Christianity, there is an ideology of motherhood that pervades scripture, ritual, and doctrine, yet there is an academic silence that means relatively little space has been given to motherhood and mothering, and even less to voluntary childlessness, from a faith perspective. By drawing on qualitative in-depth interviews with Christian women living in Britain, narrating their experiences of motherhood and voluntary childlessness, I suggest there are also lived maternal silences encountered by women in contemporary Christianity. There is a maternal expectation produced through church teaching, liturgy and culture that constructs women as ‘maternal bodies’ (Gatrell 2008; this silences and marginalises women from articulating their complex relationship with religion, motherhood, and childlessness in ways that challenge their spiritual development. However, this article also introduces the everyday and intentional tactics women employ to disrupt the maternal expectation, and hereby interrupt the maternal silence.

  15. Tacit Authorization : A Legal Solution for Administrative Silence

    NARCIS (Netherlands)

    Hoogstra, Nicole; de Graaf, K.J.

    2016-01-01

    This article discusses one of the current legal instruments to stimulate timely decision-making by administrative authorities, namely the ‘Lex silencio positivo’ or the ‘Silence is Consent’ rule. Tacit authorization prescribes that the license sought by the applicant will be granted automatically if

  16. MGMT gene silencing and benefit from temozolomide in glioblastoma

    NARCIS (Netherlands)

    Hegi, ME; Diserens, A; Gorlia, T; Hamou, M; de Tribolet, N; Weller, M; Kros, JM; Hainfellner, JA; Mason, W; Mariani, L; Bromberg, JEC; Hau, P; Mirimanoff, RO; Cairncross, JG; Janzer, RC; Stupp, R

    2005-01-01

    BACKGROUND: Epigenetic silencing of the MGMT (O(sup 6)-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship bet

  17. FCJ-156 Hacking the Social: Internet Memes, Identity Antagonism, and the Logic of Lulz.

    OpenAIRE

    Ryan M. Milner

    2013-01-01

    4chan and reddit are participatory media collectives undergirded by a “logic of lulz” that favours distanced irony and critique. It often works at the expense of core identity categories like race and gender. However, the logic need not be entirely counterproductive to public discourse. Provided that diverse identities find voice instead of exclusion, these sites may facilitate vibrant, agonistic discussion instead of disenfranchising antagonism. In order to assess this potential for producti...

  18. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system

    OpenAIRE

    Schlosburg, Joel E.; Blankman, Jacqueline L.; Long, Jonathan Z.; Daniel K Nomura; Pan, Bin; Kinsey, Steven G.; Nguyen, Peter T.; Ramesh, Divya; Booker, Lamont; Burston, James J; Thomas, Elizabeth A.; Selley, Dana E; Sim-Selley, Laura J; Liu, Qingsong; Lichtman, Aron H.

    2010-01-01

    Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. Here we show that a similar form of functional antagonism is produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to ca...

  19. Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction.

    Science.gov (United States)

    Chang, Jennifer; Fedinec, Alexander L; Kuntamallappanavar, Guruprasad; Leffler, Charles W; Bukiya, Anna N; Dopico, Alex M

    2016-01-01

    Despite preventive education, the combined consumption of alcohol and caffeine (particularly from "energy drinks") continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 µM) antagonized the endothelium-independent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40-70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS(-/-)) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 µM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without

  20. Hirsutella sinensis antagonizes the effect of aristolochic acid on human proximal tubular epithelial cells

    Institute of Scientific and Technical Information of China (English)

    张媺

    2006-01-01

    Objective To study whether Hirsutella sinensis (HS) can antagonize aristolochic acid (AA) induced fibrogenesis on human proximal tubular epithelial cells (HKC). Methods HKC were incubated with medium alone, medium with HS 10 mg/L, medium with AA-Na 40 mg/L or medium with AA-Na 40 mg/L and HS 10 mg/L, respectively. After 12 h (for mRNA) or 36 h (for protein) , cells were lysed, and the mRNA and pro-

  1. Effect of Chronic Endothelin Receptor Antagonism on Cerebrovascular Function in Type 2 Diabetes

    OpenAIRE

    Harris, Alex K; Elgebaly, Mostafa M.; Li, Weiguo; Sachidanandam, Kamakshi; Ergul, Adviye

    2008-01-01

    Diabetes increases the risk of stroke and contributes to poor clinical outcomes in this patient population. Myogenic tone of the cerebral vasculature, including basilar arteries, plays a key role in controlling cerebral blood flow. Increased myogenic tone is ameliorated with ET receptor antagonism in Type 1 diabetes. However, the role of ET-1 and its receptors in cerebrovascular dysfunction in Type-2 diabetes, a common comorbidity in stroke patients, remains poorly elucidated. Therefore, we h...

  2. β-Endorphin Antagonizes the Effects of α-MSH on Food Intake and Body Weight

    OpenAIRE

    Dutia, Roxanne; Meece, Kana; Dighe, Shveta; Kim, Andrea J.; Sharon L Wardlaw

    2012-01-01

    Proopiomelanocortin (POMC) is posttranslationally processed to several peptides including α-MSH, a primary regulator of energy balance that inhibits food intake and stimulates energy expenditure. However, another POMC-derived peptide, β-endorphin (β-EP), has been shown to stimulate food intake. In this study we examined the effects of intracerebroventricular (icv) β-EP on food intake and its ability to antagonize the negative effects of α-MSH on energy balance in male rats. A single icv injec...

  3. Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo

    DEFF Research Database (Denmark)

    Johansen, H K; Jensen, T G; Dessau, R B;

    2000-01-01

    The combination of beta-lactam antibiotics and macrolides is often recommended for the initial empirical treatment of acute pneumonia in order to obtain activity against the most important pathogens. Theoretically, this combination may be inexpedient, as the bacteriostatic agent may antagonize th...... and in vivo between penicillin and erythromycin suggests that ss-lactam antibiotics and macrolides should not be administered together unless pneumococcal infection is ruled out....

  4. One-hybrid screens at the Saccharomyces cerevisiae HMR locus identify novel transcriptional silencing factors.

    Science.gov (United States)

    Andrulis, Erik D; Zappulla, David C; Alexieva-Botcheva, Krassimira; Evangelista, Carlos; Sternglanz, Rolf

    2004-01-01

    In Saccharomyces cerevisiae, genes located at the telomeres and the HM loci are subject to transcriptional silencing. Here, we report results of screening a Gal4 DNA-binding domain hybrid library for proteins that cause silencing when targeted to a silencer-defective HMR locus. PMID:15020450

  5. Toward a science of silence: The consequences of leaving a memory unsaid

    DEFF Research Database (Denmark)

    Stone, Charles; Coman, Alin; Brown, Adam;

    2012-01-01

    the silence is intentional or unintentional, and whether the silenced memory is related or unrelated to the memories emerging in a conversation. These factors appear to be critical when considering the mnemonic consequences. Moreover, the influence of silence on memory varies between speaker and listener...

  6. The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism.

    Science.gov (United States)

    Parnell, Timothy J; Schlichter, Alisha; Wilson, Boris G; Cairns, Bradley R

    2015-01-01

    ISWI family chromatin remodelers typically organize nucleosome arrays, while SWI/SNF family remodelers (RSC) typically disorganize and eject nucleosomes, implying an antagonism that is largely unexplored in vivo. Here, we describe two independent genetic screens for rsc suppressors that yielded mutations in the promoter-focused ISW1a complex or mutations in the 'basic patch' of histone H4 (an epitope that regulates ISWI activity), strongly supporting RSC-ISW1a antagonism in vivo. RSC and ISW1a largely co-localize, and genomic nucleosome studies using rsc isw1 mutant combinations revealed opposing functions: promoters classified with a nucleosome-deficient region (NDR) gain nucleosome occupancy in rsc mutants, but this gain is attenuated in rsc isw1 double mutants. Furthermore, promoters lacking NDRs have the highest occupancy of both remodelers, consistent with regulation by nucleosome occupancy, and decreased transcription in rsc mutants. Taken together, we provide the first genetic and genomic evidence for RSC-ISW1a antagonism and reveal different mechanisms at two different promoter architectures.

  7. E2A Antagonizes PU.1 Activity through Inhibition of DNA Binding.

    Science.gov (United States)

    Rogers, Jason H; Owens, Kristin S; Kurkewich, Jeffrey; Klopfenstein, Nathan; Iyer, Sangeeta R; Simon, M Celeste; Dahl, Richard

    2016-01-01

    Antagonistic interactions between transcription factors contribute to cell fate decisions made by multipotent hematopoietic progenitor cells. Concentration of the transcription factor PU.1 affects myeloid/lymphoid development with high levels of PU.1 directing myeloid cell fate acquisition at the expense of B cell differentiation. High levels of PU.1 may be required for myelopoiesis in order to overcome inhibition of its activity by transcription factors that promote B cell development. The B cell transcription factors, E2A and EBF, are necessary for commitment of multipotential progenitors and lymphoid primed multipotential progenitors to lymphocytes. In this report we hypothesized that factors required for early B cell commitment would bind to PU.1 and antagonize its ability to induce myeloid differentiation. We investigated whether E2A and/or EBF associate with PU.1. We observed that the E2A component, E47, but not EBF, directly binds to PU.1. Additionally E47 represses PU.1-dependent transactivation of the MCSFR promoter through antagonizing PU.1's ability to bind to DNA. Exogenous E47 expression in hematopoietic cells inhibits myeloid differentiation. Our data suggest that E2A antagonism of PU.1 activity contributes to its ability to commit multipotential hematopoietic progenitors to the lymphoid lineages.

  8. Trans-specific gene silencing between host and parasitic plants.

    Science.gov (United States)

    Tomilov, Alexey A; Tomilova, Natalia B; Wroblewski, Tadeusz; Michelmore, Richard; Yoder, John I

    2008-11-01

    Species of Orobanchaceae parasitize the roots of nearby host plants to rob them of water and other nutrients. Parasitism can be debilitating to the host plant, and some of the world's most pernicious agricultural pests are parasitic weeds. We demonstrate here that interfering hairpin constructs transformed into host plants can silence expression of the targeted genes in the parasite. Transgenic roots of the hemi-parasitic plant Triphysaria versicolor expressing the GUS reporter gene were allowed to parasitize transgenic lettuce roots expressing a hairpin RNA containing a fragment of the GUS gene (hpGUS). When stained for GUS activity, Triphysaria roots attached to non-transgenic lettuce showed full GUS activity, but those parasitizing transgenic hpGUS lettuce lacked activity in root tissues distal to the haustorium. Transcript quantification indicated a reduction in the steady-state level of GUS mRNA in Triphysaria when they were attached to hpGUS lettuce. These results demonstrate that the GUS silencing signal generated by the host roots was translocated across the haustorium interface and was functional in the parasite. Movement across the haustorium was bi-directional, as demonstrated in double-junction experiments in which non-transgenic Triphysaria concomitantly parasitized two hosts, one transgenic for hpGUS and the other transgenic for a functional GUS gene. Observation of GUS silencing in the second host demonstrated that the silencing trigger could be moved from one host to another using the parasite as a physiological bridge. Silencing of parasite genes by generating siRNAs in the host provides a novel strategy for controlling parasitic weeds. PMID:18643992

  9. Antagonism between abscisic acid and gibberellins is partially mediated by ascorbic acid during seed germination in rice

    OpenAIRE

    Ye, Nenghui; Zhang, Jianhua

    2012-01-01

    The antagonism between abscisic acid (ABA) and gibberellin (GA) plays a key role in controlling seed germination,1,2 but the mechanism of antagonism during this process is not known. In the associated study,3 we investigated the relationship among ABA, reactive oxygen species (ROS), ascorbic acid (ASC) and GA during rice seed germination. ROS production is reduced by ABA, which hence results in decreasing ASC accumulation during imbibition. GA accumulation was also suppressed by a reduced ROS...

  10. Experimental testing of Mackay's model for functional antagonism in the isolated costo-uterus of the rat.

    OpenAIRE

    Henry, P. J.; Lulich, K M; Paterson, J W

    1985-01-01

    Several key predictions of a recently developed model for functional antagonism (Mackay, 1981) were experimentally tested using the rat isolated costo-uterine preparation. In the presence of the functional antagonist fenoterol (Fen), the functional constants (KAF) for carbachol and oxotremorine (Oxo) were respectively 9.9 and 3.4 fold greater than their corresponding affinity constants (KA). According to Mackay's model for functional antagonism, the higher KAF/KA ratio for carbachol indicates...

  11. Three distinct suppressors of RNA silencing encoded by a 20-kb viral RNA genome

    Science.gov (United States)

    Lu, Rui; Folimonov, Alexey; Shintaku, Michael; Li, Wan-Xiang; Falk, Bryce W.; Dawson, William O.; Ding, Shou-Wei

    2004-11-01

    Viral infection in both plant and invertebrate hosts requires a virus-encoded function to block the RNA silencing antiviral defense. Here, we report the identification and characterization of three distinct suppressors of RNA silencing encoded by the 20-kb plus-strand RNA genome of citrus tristeza virus (CTV). When introduced by genetic crosses into plants carrying a silencing transgene, both p20 and p23, but not coat protein (CP), restored expression of the transgene. Although none of the CTV proteins prevented DNA methylation of the transgene, export of the silencing signal (capable of mediating intercellular silencing spread) was detected only from the F1 plants expressing p23 and not from the CP- or p20-expressing F1 plants, demonstrating suppression of intercellular silencing by CP and p20 but not by p23. Thus, intracellular and intercellular silencing are each targeted by a CTV protein, whereas the third, p20, inhibits silencing at both levels. Notably, CP suppresses intercellular silencing without interfering with intracellular silencing. The novel property of CP suggests a mechanism distinct to p20 and all of the other viral suppressors known to interfere with intercellular silencing and that this class of viral suppressors may not be consistently identified by Agrobacterium coinfiltration because it also induces RNA silencing against the infiltrated suppressor transgene. Our analyses reveal a sophisticated viral counter-defense strategy that targets the silencing antiviral pathway at multiple steps and may be essential for protecting CTV with such a large RNA genome from antiviral silencing in the perennial tree host. RNA interference | citrus tristeza virus | virus synergy | antiviral immunity

  12. Silences and moral narratives: infanticide as reproductive disruption.

    Science.gov (United States)

    Aengst, Jennifer

    2014-01-01

    Infanticide is a widespread practice, yet few ethnographic and theoretical works examine this. Drawing on ethnographic research conducted in the Indian Himalayas, I argue that infanticide is a form of reproductive disruption that elicits both public moral judgments and private silences. In this Himalayan context, the stigmas of abortion and premarital sex prevent community acknowledgement of infanticide and baby abandonment. Unmarried women hide their pregnancies, deliver and abandon their babies, and later are rushed to the hospital with postdelivery complications. While biomedical doctors deal with the debris of infanticide (postpartum hemorrhage), there is no formal accounting of the practice. I argue that by regarding infanticide as a form of reproductive disruption, we can open up women's narratives of pain and suffering that are silenced because of moral repugnance.

  13. Attachment issues: kinetochore transformations and spindle checkpoint silencing.

    Science.gov (United States)

    Etemad, Banafsheh; Kops, Geert J P L

    2016-04-01

    Cell division culminates in the segregation of duplicated chromosomes in opposite directions prior to cellular fission. This process is guarded by the spindle assembly checkpoint (SAC), which prevents the anaphase of cell division until stable connections between spindle microtubules and the kinetochores of all chromosomes are established. The anaphase inhibitor is generated at unattached kinetochores and inhibitor production is prevented when microtubules are captured. Understanding the molecular changes in the kinetochore that are evoked by microtubule attachments is crucial for understanding the mechanisms of SAC signaling and silencing. Here, we highlight the most recent findings on these events, pinpoint some remaining mysteries, and argue for incorporating holistic views of kinetochore dynamics in order to understand SAC silencing. PMID:26947988

  14. Bacterial Cellular Engineering by Genome Editing and Gene Silencing

    Directory of Open Access Journals (Sweden)

    Nobutaka Nakashima

    2014-02-01

    Full Text Available Genome editing is an important technology for bacterial cellular engineering, which is commonly conducted by homologous recombination-based procedures, including gene knockout (disruption, knock-in (insertion, and allelic exchange. In addition, some new recombination-independent approaches have emerged that utilize catalytic RNAs, artificial nucleases, nucleic acid analogs, and peptide nucleic acids. Apart from these methods, which directly modify the genomic structure, an alternative approach is to conditionally modify the gene expression profile at the posttranscriptional level without altering the genomes. This is performed by expressing antisense RNAs to knock down (silence target mRNAs in vivo. This review describes the features and recent advances on methods used in genomic engineering and silencing technologies that are advantageously used for bacterial cellular engineering.

  15. The weight of the word: knowing silences in obesity research.

    Science.gov (United States)

    Warin, Megan J; Gunson, Jessica S

    2013-12-01

    In this article, we examine the ethical and methodological tensions entailed in doing qualitative research in obesity studies. Framing our own embodied engagements through critical social theory, we consider how cultural meanings associated with obesity are silenced and negotiated in the research process. This negotiation is fraught with linguistic and corporeal challenges, beginning with the decision to use (or not use) the word obesity in research materials. Obesity is a visible stigma, and we argue that silencing language does not erase the tacit judgments that accompany discursive categorization. It is in a broader context of power relations that we examine the relationship between researcher and participant bodies and the ways in which collective knowingness about fat bodies underpins methodological engagement. The simultaneous presence and absence of obesity have a significant impact on the research process, in shaping both participants' experiences and the researcher's actions and interpretations. PMID:24159004

  16. Els pedagògics sons dels silencis. Enllà del silenci d’Auschwitz Los pedagógicos sonidos de los silencios. Más allá del silencio de Auschwitz The pedagogical sounds of silences. Beyond the silence of Auschwitz

    Directory of Open Access Journals (Sweden)

    Marta Burguet Arfelis

    2009-01-01

    Full Text Available Després del gran silenci d’Auschwitz, en aquest passeig pedagògic descriptiu pels sons dels silencis, ens introduïm en les semàntiques dels silencis, acceptant la seva polisèmia i descrivintne algunes de les accepcions més vinculades a l’àmbit educatiu. S’analitza, d’una banda, la genealogia dels silencis, algunes de les seves claus d’origen, i de l’altra, la teleologia dels silencis, la finalitat, pedagògica o no, dels mateixos. Alhora, partint del silenci com a valor pedagògic en aquesta educació al llarg de tota la vida, es proposen cinc etapes progressives per treballar pedagògicament els silencis, tot apostant per un salt qualitatiu axiològic entre el silenci com a estadi –estar en silenci– i el silenci com a seïtat –ser silenci–. _____________________________________________ Après le grand silence d’Auschwitz, dans ce passage de pédagogie descriptive par les sons des silences, nous nous introduisons dans les sémantiques des silences, en acceptant leur polysémie et en en décrivant certaines acceptions parmi les plus étroitement liées au domaine éducatif. Nous analysons, d’une part, la généalogie des silences, certaines de leur clés d’origine et, de l’autre, la téléologie des silences, et leur finalité, pédagogique ou non. Parallèlement, en partant du silence en tant que valeur pédagogique dans cette éducation tout au long de la vie, nous proposons cinq étapes progressives dans lesquelles travailler pédagogiquement les silences, tout en faisant le pari d’un saut qualitatif axiologique entre le silence en tant qu’état —demeurer en silence— et le silence en tant que manière d’être —être silencieux.Después del gran silencio de Auschwitz, en este paseo pedagógico descriptivo por los sonidos de los silencios nos introducimos en las semánticas de los silencios, aceptando su polisemia i describiendo algunas de las acepciones más vinculadas al ámbito educativo. Se

  17. Hearing the Silence: Children’s Voices on Violence

    OpenAIRE

    Collins, Kathryn S.

    2003-01-01

    Each year more than five million children in the United States are exposed to traumatizing events in their communities. This paper presents a discussion of multiple areas in violence and victimization research that needs to be continued as well as provides suggestions on how to un-silence child survivors through bridging the gaps between research and practice. It reviews the overarching problem of violence in the U.S. at the domestic and global levels and the effects of victimi...

  18. Optical silencing of C. elegans cells with arch proton pump.

    Directory of Open Access Journals (Sweden)

    Ayako Okazaki

    Full Text Available BACKGROUND: Optogenetic techniques using light-driven ion channels or ion pumps for controlling excitable cells have greatly facilitated the investigation of nervous systems in vivo. A model organism, C. elegans, with its small transparent body and well-characterized neural circuits, is especially suitable for optogenetic analyses. METHODOLOGY/PRINCIPAL FINDINGS: We describe the application of archaerhodopsin-3 (Arch, a recently reported optical neuronal silencer, to C. elegans. Arch::GFP expressed either in all neurons or body wall muscles of the entire body by means of transgenes were localized, at least partially, to the cell membrane without adverse effects, and caused locomotory paralysis of worms when illuminated by green light (550 nm. Pan-neuronal expression of Arch endowed worms with quick and sustained responsiveness to such light. Worms reliably responded to repeated periods of illumination and non-illumination, and remained paralyzed under continuous illumination for 30 seconds. Worms expressing Arch in different subsets of motor neurons exhibited distinct defects in the locomotory behavior under green light: selective silencing of A-type motor neurons affected backward movement while silencing of B-type motor neurons affected forward movement more severely. Our experiments using a heat-shock-mediated induction system also indicate that Arch becomes fully functional only 12 hours after induction and remains functional for more than 24 hour. CONCLUSIONS/SGNIFICANCE: Arch can be used for silencing neurons and muscles, and may be a useful alternative to currently widely used halorhodopsin (NpHR in optogenetic studies of C. elegans.

  19. Drum silencer with shallow cavity filled with helium.

    Science.gov (United States)

    Choy, Y S; Huang, Lixi

    2003-09-01

    The motivation of this study is twofold: (a) to produce a flow-through silencer with zero pressure loss for pressure-critical applications, and (b) to tackle low frequency noise with limited sideway space using cavities filled with helium. The work represents a further development of our recently conceived device of a drum-like silencer with conventional air cavity [Huang, J. Acoust. Soc. Am. 112, 2014-2025 (2002); Choy and Huang, ibid. 112, 2026-2035 (2002)]. Theoretical predictions are validated by experimental data. The new silencer consists of two highly tensioned membranes lining part of a duct, and each membrane is backed by a cavity filled with helium. For a typical configuration of a duct with height h, membrane length L = 7h, cavity depth h = 0.2h, and tension T = 0.52rho0c0(2)h2, where rho0 and c0 are the ambient density and speed of sound in air, respectively, the transmission loss has a continuous stop band of TL > 6.35 dB for frequency 0.03c0/h to 0.064c0/h, which is much better than traditional duct lining. In addition to the mechanisms at work for drum silencers with air cavity, the low density of helium reduces the masslike reactance of the cavity on the second in vacuo mode of membrane vibration. The reduction greatly enhances the membrane response at this mode, which is found to be critical for achieving a broadband performance in the low-frequency regime.

  20. Epigenetic silencing of CYP24 in the tumor microenvironment

    OpenAIRE

    Johnson, Candace S.; Chung, Ivy; Trump, Donald L.

    2010-01-01

    Calcitriol (1,25 dihydroxycholecalciferol) has significant antitumor activity in vitro and in vivo in a number of tumor model systems. We developed a system for isolation of fresh endothelial cells from tumors and Matrigel environments which demonstrate that CYP24, the catabolic enzyme involved in vitamin D signaling, is epigenetically silenced selectively in tumor-derived endothelial cells (TDEC). TDEC maintain phenotypic characteristics which are distinct from endothelial cells isolated fro...

  1. Silencing Deafness: Displacing Disability in the Nineteenth Century

    Directory of Open Access Journals (Sweden)

    Esme Cleall

    2015-03-01

    Full Text Available This article traces the way in which the language of displacement and silence were used in nineteenth-century discussions of deafness and connects this tendency to the marginalised place deaf experience occupies historically. Throughout the nineteenth century, a period which saw the consolidation of ‘the deaf and dumb’ as a social category, the word ‘forgetting’ crept into numerous discussions of deafness by both deaf and hearing commentators. Some, such as the educationalist Alexander Graeme Bell, were overt in their desire to forget deafness, demanding disability was ‘bred out’ and deaf culture condemned to the forgotten past. Others used the term ambivalently and sometimes metaphorically discussing the deaf as ‘forgotten’ by society, and ‘children of silence’. Some even pleaded that people who were deaf were not forgotten. But, though varied, the use of the imagery of forgetting and silence to evoke deafness is recurrent, and may, therefore, be seen to reveal something about how deaf experience can be approached as a displacement where deafness was spatially and imaginatively marginalised. I argue that one of the consequences of the conceptual framing of deafness through the language of forgetting was actively to silence deafness and to neutralise the idea that disability should be marginal and could be forgotten.

  2. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential.

    Science.gov (United States)

    Kazanets, Anna; Shorstova, Tatiana; Hilmi, Khalid; Marques, Maud; Witcher, Michael

    2016-04-01

    Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes. PMID:27085853

  3. Virus-induced Gene Silencing in Eggplant (Solanum melongena)

    Institute of Scientific and Technical Information of China (English)

    HaipingLiu; Daqi Fu; Benzhong Zhu; Huaxue Yan; Xiaoying Shen; Jinhua Zuo; Yi Zhu; Yunbo Luo

    2012-01-01

    Eggplant (Solanum melongena) is an economically important vegetable requiring investigation into its various genomic functions.The current limitation in the investigation of genomic function in eggplant is the lack of effective tools available for conducting functional assays.Virus-induced gene silencing (VIGS) has played a critical role in the functional genetic analyses.In this paper,TRV-mediated VIGS was successfully elicited in eggplant.We first cloned the CDS sequence of PDS (PHYTOENE DESATURASE) in eggplant and then silenced the PDS gene.Photo-bleaching was shown on the newly-developed leaves four weeks after agroinoculation,indicating that VIGS can be used to silence genes in eggplant.To further illustrate the reliability of VIGS in eggplant,we selected Chl H,Su and CLA1 as reporters to elicit VIGS using the high-pressure spray method.Suppression of Chl H and Su led to yellow leaves,while the depletion of CLA1 resulted in albino.In conclusion,four genes,PDS,Chl H,Su (Sulfur),CLA1,were down-regulated significantly by VIGS,indicating that the VIGS system can be successfully applied in eggplant and is a reliable tool for the study of gene function.

  4. Right to Silence%沉默权论要

    Institute of Scientific and Technical Information of China (English)

    朱华

    2012-01-01

    Right to silence in the criminal procedure law is a human rights protection system that can basically make a balance between the public authority of the State and the right to freedom of statement of suspects and defendants.Dealing well with the relationship between the right to silence and the right of questioning can help to improve objectivity and accuracy of criminal cases and reduce trumped-up cases caused by torture.The relative implied right to silence is the result of the development of modern civilization and the rule of law,and conforms to China's basic national condition and current status.%刑事诉讼法中的沉默权,是国家公权力与嫌疑人、被告人陈述自由权得到基本平衡的人权保障制度。处理好沉默权与讯问权的关系,有利于提高刑事案件的客观性和准确性,减少因刑讯逼供产生的冤假错案,默示的相对沉默权,是现代文明法治发展的结果,符合我国基本国情及现状。

  5. Hybrid silencers with micro-perforated panels and internal partitions.

    Science.gov (United States)

    Yu, Xiang; Cheng, Li; You, Xiangyu

    2015-02-01

    A sub-structuring approach, along with a unit cell treatment, is proposed to model expansion chamber silencers with internal partitions and micro-perforated panels (MPPs) in the absence of internal flow. The side-branch of the silencer is treated as a combination of unit cells connected in series. It is shown that, by connecting multiple unit cells with varying parameters, the noise attenuation bandwidth can be enlarged. With MPPs, the hybrid noise attenuation mechanism of the silencer is revealed. Depending on the size of the perforation hole, noise attenuation can be dominated by dissipative, reactive, or combined effects together. For a broadband sound absorption, the hole size, together with the perforation ratio and other parameters, can be optimized to strike a balance between the dissipative and reactive effect, for ultimately achieving the desired noise attenuation performance within a prescribed frequency region. The modular nature of the proposed formulation allows doing this in a flexible, accurate, and cost effective manner. The accuracy of the proposed approach is validated through comparisons with finite element method and experiments.

  6. Exploring the spiral of silence in adjustable social networks

    Science.gov (United States)

    Wu, Yue; Du, Ya-Jun; Li, Xian-Yong; Chen, Xiao-Liang

    2015-03-01

    This study extends the understanding of the spiral of silence theory by taking into account four factors, including the topology of networks, the time factor of information transmission, the node degree of individuals and the freedom of expression. Simulation experiments analyze the silencers, public opinion in steady state and relaxation time in small-world networks, scale-free networks and community-structured networks by adjusting the initial conditions. Results highlight that individuals are easier to keep silent in scale-free network, especially when the individual with big degree and minority opinion starts the discussion. Conversely, there are only a few individuals keep silent in the community-structured network when the two communities hold opposite opinions. Moreover, the number of silencers grows as the degree of coupling increases, and it decreases as the freedom of expression goes up. By analyzing the public opinion evolution, we also find some important conditions, such as the network topology, the potential public opinion distribution, and the status and sides of the first speaker, can drive the minority reversal.

  7. Epigenetic silencing of CYP24 in the tumor microenvironment

    Science.gov (United States)

    Johnson, Candace S.; Chung, Ivy; Trump, Donald L.

    2010-01-01

    Calcitriol (1,25 dihydroxycholecalciferol) has significant antitumor activity in vitro and in vivo in a number of tumor model systems. We developed a system for isolation of fresh endothelial cells from tumors and Matrigel environments which demonstrate that CYP24, the catabolic enzyme involved in vitamin D signaling, is epigenetically silenced selectively in tumor-derived endothelial cells (TDEC). TDEC maintain phenotypic characteristics which are distinct from endothelial cells isolated from normal tissues and from Matrigel plugs (MDEC). In TDEC, calcitriol induces G0/G1 arrest, modulates p27 and p21, and induces apoptotic cell death and decreases P-Erk and P-Akt. In contrast, endothelial cells isolated from normal tissues and MDEC are unresponsive to calcitriol-mediated anti-proliferative effects despite intact signaling through the vitamin D receptor (VDR). In TDEC, which is sensitive to calcitriol, the CYP24 promoter is hypermethylated in two CpG island regions located at the 5′end; this hypermethylation may contribute to gene silencing of CYP24. The extent of methylation in these two regions is significantly less in MDEC. Lastly, treatment of TDEC with a DNA methyltransferase inhibitor restores calcitriol-mediated induction of CYP24 and resistance to calcitriol. These data suggest that epigenetic silencing of CYP24 modulates cellular responses to calcitriol. PMID:20304059

  8. Epigenetic silencing of Plasmodium falciparum genes linked to erythrocyte invasion.

    Directory of Open Access Journals (Sweden)

    Alfred Cortés

    2007-08-01

    Full Text Available The process of erythrocyte invasion by merozoites of Plasmodium falciparum involves multiple steps, including the formation of a moving junction between parasite and host cell, and it is characterised by the redundancy of many of the receptor-ligand interactions involved. Several parasite proteins that interact with erythrocyte receptors or participate in other steps of invasion are encoded by small subtelomerically located gene families of four to seven members. We report here that members of the eba, rhoph1/clag, acbp, and pfRh multigene families exist in either an active or a silenced state. In the case of two members of the rhoph1/clag family, clag3.1 and clag3.2, expression was mutually exclusive. Silencing was clonally transmitted and occurred in the absence of detectable DNA alterations, suggesting that it is epigenetic. This was demonstrated for eba-140. Our data demonstrate that variant or mutually exclusive expression and epigenetic silencing in Plasmodium are not unique to genes such as var, which encode proteins that are exported to the surface of the erythrocyte, but also occur for genes involved in host cell invasion. Clonal variant expression of invasion-related ligands increases the flexibility of the parasite to adapt to its human host.

  9. Structural basis for the antiviral activity of BST-2/tetherin and its viral antagonism

    Directory of Open Access Journals (Sweden)

    Juan F. eArias

    2011-12-01

    Full Text Available The interferon-inducible host restriction factor bone marrow stromal antigen 2 (BST-2/tetherin blocks the release of HIV-1 and other enveloped viruses. In turn, these viruses have evolved specific antagonists to counteract this host antiviral molecule, such as the HIV-1 protein Vpu. BST-2 is a type II transmembrane protein with an unusual topology consisting of an N-terminal cytoplasmic tail (CT followed by a single transmembrane (TM domain, a coiled-coil extracellular (EC domain, and a glycosylphosphatidylinositol (GPI anchor at the C terminus. We and others showed that BST-2 restricts enveloped virus release by bridging the host and virion membranes with its two opposing membrane anchors and that deletion of either one completely abrogates antiviral activity. The EC domain also shows conserved structural properties that are required for antiviral function. It contains several destabilizing amino acids that confer the molecule with conformational flexibility to sustain the protein's function as a virion tether, and three conserved cysteine residues that mediate homodimerization of BST-2, as well as acting as a molecular ruler that separates the membrane anchors. Conversely, the efficient release of virions is promoted by the HIV-1 Vpu protein and other viral antagonists. Our group and others provided evidence from mutational analyses indicating that Vpu antagonism of BST-2-mediated viral restriction requires a highly specific interaction of their mutual TM domains. This interpretation is further supported and expanded by the findings of the latest structural modeling studies showing that critical amino acids in a conserved helical face of these TM domains are required for Vpu-BST-2 interaction and antagonism. In this review, we summarize the current advances in our understanding of the structural basis for BST-2 antiviral function as well as BST-2-specific viral antagonism.

  10. Genomic conflicts and sexual antagonism in human health: insights from oxytocin and testosterone.

    Science.gov (United States)

    Mokkonen, Mikael; Crespi, Bernard J

    2015-04-01

    We review the hypothesized and observed effects of two of the major forms of genomic conflicts, genomic imprinting and sexual antagonism, on human health. We focus on phenotypes mediated by peptide and steroid hormones (especially oxytocin and testosterone) because such hormones centrally mediate patterns of physical and behavioral resource allocation that underlie both forms of conflict. In early development, a suite of imprinted genes modulates the human oxytocinergic system as predicted from theory, with paternally inherited gene expression associated with higher oxytocin production, and increased solicitation to mothers by infants. This system is predicted to impact health through the incompatibility of paternal-gene and maternal-gene optima and increased vulnerability of imprinted gene systems to genetic and epigenetic changes. Early alterations to oxytocinergic systems have long-term negative impacts on human psychological health, especially through their effects on attachment and social behavior. In contrast to genomic imprinting, which generates maladaptation along an axis of mother-infant attachment, sexual antagonism is predicted from theory to generate maladaptation along an axis of sexual dimorphism, modulated by steroid and peptide hormones. We describe evidence of sexual antagonism from studies of humans and other animals, demonstrating that sexually antagonistic effects on sex-dimorphic phenotypes, including aspects of immunity, life history, psychology, and behavior, are commonly observed and lead to forms of maladaptation that are demonstrated, or expected, to impact human health. Recent epidemiological and psychiatric studies of schizophrenia in particular indicate that it is mediated, in part, by sexually antagonistic alleles. The primary implication of this review is that data collection focused on (i) effects of imprinted genes that modulate the oxytocin system, and (ii) effects of sexually antagonistic alleles on sex-dimorphic, disease

  11. Genomic conflicts and sexual antagonism in human health: insights from oxytocin and testosterone.

    Science.gov (United States)

    Mokkonen, Mikael; Crespi, Bernard J

    2015-04-01

    We review the hypothesized and observed effects of two of the major forms of genomic conflicts, genomic imprinting and sexual antagonism, on human health. We focus on phenotypes mediated by peptide and steroid hormones (especially oxytocin and testosterone) because such hormones centrally mediate patterns of physical and behavioral resource allocation that underlie both forms of conflict. In early development, a suite of imprinted genes modulates the human oxytocinergic system as predicted from theory, with paternally inherited gene expression associated with higher oxytocin production, and increased solicitation to mothers by infants. This system is predicted to impact health through the incompatibility of paternal-gene and maternal-gene optima and increased vulnerability of imprinted gene systems to genetic and epigenetic changes. Early alterations to oxytocinergic systems have long-term negative impacts on human psychological health, especially through their effects on attachment and social behavior. In contrast to genomic imprinting, which generates maladaptation along an axis of mother-infant attachment, sexual antagonism is predicted from theory to generate maladaptation along an axis of sexual dimorphism, modulated by steroid and peptide hormones. We describe evidence of sexual antagonism from studies of humans and other animals, demonstrating that sexually antagonistic effects on sex-dimorphic phenotypes, including aspects of immunity, life history, psychology, and behavior, are commonly observed and lead to forms of maladaptation that are demonstrated, or expected, to impact human health. Recent epidemiological and psychiatric studies of schizophrenia in particular indicate that it is mediated, in part, by sexually antagonistic alleles. The primary implication of this review is that data collection focused on (i) effects of imprinted genes that modulate the oxytocin system, and (ii) effects of sexually antagonistic alleles on sex-dimorphic, disease

  12. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    OpenAIRE

    Christine eDugovic; Shelton, Jonathan E.; Sujin eYun; Pascal eBonaventure; Shireman, Brock T.; Lovenberg, Timothy W.

    2014-01-01

    In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagon...

  13. Disruption of Cell-to-Cell Signaling Does Not Abolish the Antagonism of Phaeobacter gallaeciensis toward the Fish Pathogen Vibrio anguillarum in Algal Systems

    DEFF Research Database (Denmark)

    Prol García, María Jesús; D'Alvise, Paul; Gram, Lone

    2013-01-01

    Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic Phaeobac......Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic...

  14. DICER-LIKE2 plays a primary role in transitive silencing of transgenes in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Sizolwenkosi Mlotshwa

    Full Text Available Dicer-like (DCL enzymes play a pivotal role in RNA silencing in plants, processing the long double-stranded RNA (dsRNA that triggers silencing into the primary short interfering RNAs (siRNAs that mediate it. The siRNA population can be augmented and silencing amplified via transitivity, an RNA-dependent RNA polymerase (RDR-dependent pathway that uses the target RNA as substrate to generate secondary siRNAs. Here we report that Arabidopsis DCL2-but not DCL4-is required for transitivity in cell-autonomous, post-transcriptional silencing of transgenes. An insertion mutation in DCL2 blocked sense transgene-induced silencing and eliminated accumulation of the associated RDR-dependent siRNAs. In hairpin transgene-induced silencing, the dcl2 mutation likewise eliminated accumulation of secondary siRNAs and blocked transitive silencing, but did not block silencing mediated by primary siRNAs. Strikingly, in all cases, the dcl2 mutation eliminated accumulation of all secondary siRNAs, including those generated by other DCL enzymes. In contrast, mutations in DCL4 promoted a dramatic shift to transitive silencing in the case of the hairpin transgene and enhanced silencing induced by the sense transgene. Suppression of hairpin and sense transgene silencing by the P1/HC-Pro and P38 viral suppressors was associated with elimination of secondary siRNA accumulation, but the suppressors did not block processing of the stem of the hairpin transcript into primary siRNAs. Thus, these viral suppressors resemble the dcl2 mutation in their effects on siRNA biogenesis. We conclude that DCL2 plays an essential, as opposed to redundant, role in transitive silencing of transgenes and may play a more important role in silencing of viruses than currently thought.

  15. Sexual antagonism and meiotic drive cause stable linkage disequilibrium and favour reduced recombination on the X chromosome.

    Science.gov (United States)

    Rydzewski, W T; Carioscia, S A; Liévano, G; Lynch, V D; Patten, M M

    2016-06-01

    Sexual antagonism and meiotic drive are sex-specific evolutionary forces with the potential to shape genomic architecture. Previous theory has found that pairing two sexually antagonistic loci or combining sexual antagonism with meiotic drive at linked autosomal loci augments genetic variation, produces stable linkage disequilibrium (LD) and favours reduced recombination. However, the influence of these two forces has not been examined on the X chromosome, which is thought to be enriched for sexual antagonism and meiotic drive. We investigate the evolution of the X chromosome under both sexual antagonism and meiotic drive with two models: in one, both loci experience sexual antagonism; in the other, we pair a meiotic drive locus with a sexually antagonistic locus. We find that LD arises between the two loci in both models, even when the two loci freely recombine in females and that driving haplotypes will be enriched for male-beneficial alleles, further skewing sex ratios in these populations. We introduce a new measure of LD, Dz', which accounts for population allele frequencies and is appropriate for instances where these are sex specific. Both models demonstrate that natural selection favours modifiers that reduce the recombination rate. These results inform observed patterns of congealment found on driving X chromosomes and have implications for patterns of natural variation and the evolution of recombination rates on the X chromosome.

  16. Suffering in silence: Investigating the role of fear in the relationship between abusive supervision and defensive silence.

    Science.gov (United States)

    Kiewitz, Christian; Restubog, Simon Lloyd D; Shoss, Mindy K; Garcia, Patrick Raymund James M; Tang, Robert L

    2016-05-01

    Drawing from an approach-avoidance perspective, we examine the relationships between subordinates' perceptions of abusive supervision, fear, defensive silence, and ultimately abusive supervision at a later time point. We also account for the effects of subordinates' assertiveness and individual perceptions of a climate of fear on these predicted mediated relationships. We test this moderated mediation model with data from three studies involving different sources collected across various measurement periods. Results corroborated our predictions by showing (a) a significant association between abusive supervision and subordinates' fear, (b) second-stage moderation effects of subordinates' assertiveness and their individual perceptions of a climate of fear in the abusive supervision-fear-defensive silence relationship (with lower assertiveness and higher levels of climate-of-fear perceptions exacerbating the detrimental effects of fear resulting from abusive supervision), and (c) first-stage moderation effects of subordinates' assertiveness and climate-of-fear perceptions in a model linking fear to defensive silence and abusive supervision at a later time. Theoretical and practical implications are discussed. (PsycINFO Database Record PMID:26727209

  17. Technical advances in trigger-induced RNA interference gene silencing in the parasite Entamoeba histolytica.

    Science.gov (United States)

    Khalil, Mohamed I; Foda, Bardees M; Suresh, Susmitha; Singh, Upinder

    2016-03-01

    Entamoeba histolytica has a robust endogenous RNA interference (RNAi) pathway. There are abundant 27 nucleotide (nt) anti-sense small RNAs (AS sRNAs) that target genes for silencing and the genome encodes many genes involved in the RNAi pathway such as Argonaute proteins. Importantly, an E. histolytica gene with numerous AS sRNAs can function as a "trigger" to induce silencing of a gene that is fused to the trigger. Thus, the amebic RNAi pathway regulates gene expression relevant to amebic biology and has additionally been harnessed as a tool for genetic manipulation. In this study we have further improved the trigger-induced gene silencing method. We demonstrate that rather than using the full-length gene, a short portion of the coding region fused to a trigger is sufficient to induce silencing; the first 537 bp of the E. histolytica rhomboid gene (EhROM1) fused in-frame to the trigger was sufficient to silence EhROM1. We also demonstrated that the trigger method could silence two amebic genes concomitantly; fusion of the coding regions of EhROM1 and transcription factor, EhMyb, in-frame to a trigger gene resulted in both genes being silenced. Alternatively, two genes can be silenced sequentially: EhROM1-silenced parasites with no drug selection plasmid were transfected with trigger-EhMyb, resulting in parasites with both EhROM1 and EhMyb silenced. With all approaches tested, the trigger-mediated silencing was substantive and silencing was maintained despite loss of the G418 selectable marker. All gene silencing was associated with generation of AS sRNAs to the silenced gene. We tested the reversibility of the trigger system using inhibitors of histone modifications but found that the silencing was highly stable. This work represents a technical advance in the trigger gene silencing method in E. histolytica. Approaches that readily silence multiple genes add significantly to the genetic toolkit available to the ameba research community. PMID:26747561

  18. Gene silencing: Double-stranded RNA mediated mRNA degradation and gene inactivation

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The recent development of gene transfer approaches in plants and animals has revealed that transgene can undergo silencing after integration in the genome. Host genes can also be silenced as a consequence of the presence of a homologous transgene. More and more investigations have demonstrated that doublestranded RNA can silence genes by triggering degradation of homologous RNA in the cytoplasm and by directing methylation of homologous nuclear DNA sequences. Analyses of Arabidopsis mutants and plant viral suppressors of silencing are unraveling RNA-silencing mechanisms and are assessing the role of methylation in transcriptional and posttranscriptional gene silencing. This review will focus on double-stranded RNA mediated mRNA degradation and gene inactivation in plants.

  19. Antagonism by hemoglobin of effects induced by L-arginine in neuromuscular preparations from rats

    Directory of Open Access Journals (Sweden)

    C.R. Ambiel

    2001-04-01

    Full Text Available Nitric oxide (NO-synthase is present in diaphragm, phrenic nerve and vascular smooth muscle. It has been shown that the NO precursor L-arginine (L-Arg at the presynaptic level increases the amplitude of muscular contraction (AMC and induces tetanic fade when the muscle is indirectly stimulated at low and high frequencies, respectively. However, the precursor in muscle reduces AMC and maximal tetanic fade when the preparations are stimulated directly. In the present study the importance of NO synthesized in different tissues for the L-Arg-induced neuromuscular effects was investigated. Hemoglobin (50 nM did not produce any neuromuscular effect, but antagonized the increase in AMC and tetanic fade induced by L-Arg (9.4 mM in rat phrenic nerve-diaphragm preparations. D-Arg (9.4 mM did not produce any effect when preparations were stimulated indirectly at low or high frequency. Hemoglobin did not inhibit the decrease of AMC or the reduction in maximal tetanic tension induced by L-Arg in preparations previously paralyzed with d-tubocurarine and directly stimulated. Since only the presynaptic effects induced by L-Arg were antagonized by hemoglobin, the present results suggest that NO synthesized in muscle acts on nerve and skeletal muscle. Nevertheless, NO produced in nerve and vascular smooth muscle does not seem to act on skeletal muscle.

  20. Mechanism of INF-γ antagonizing pulmonary fibroblast proliferation stimulated by 60Co γ-rays

    International Nuclear Information System (INIS)

    Objective: To explore the mechanism of IFN-γ antagonizing human pulmonary fibroblasts (HLF) proliferation stimulated by 60Co γ-rays. Methods: The time- and dose-effect of HLF proliferation promoted by TGF-β1 and rat serum after radiation as well as effect of IFN-γ on proliferation were observed by MTT colorimetric methods. Content of TGF-β1 in rat serum and pulmonary tissues after irradiation as well as the effect of IFN-γ on rat serum after radiation promoting HLF to synthesize TGF-β1 were determined by ELISA. Results: TGF-β1 played a role in promoting HLF proliferation. The sera of irradiated rats could promote HLF proliferation and TGF-β1 synthesis, but the effect was inhibited by IFN-γ significantly (P<0.05). The level of TGF-β1 in rat serum and lung tissues gradually increased from 1 to 4 weeks after irradiation. Conclusions: TGF-β1 is involved in the process of γ-rays stimulating HLF proliferation, while IFN-γ can inhibit HLF from synthesizing TGF-β1 and antagonize its role of promoting HLF proliferation. (authors)

  1. Dynamical transitions in a pollination-herbivory interaction: a conflict between mutualism and antagonism.

    Directory of Open Access Journals (Sweden)

    Tomás A Revilla

    Full Text Available Plant-pollinator associations are often seen as purely mutualistic, while in reality they can be more complex. Indeed they may also display a diverse array of antagonistic interactions, such as competition and victim-exploiter interactions. In some cases mutualistic and antagonistic interactions are carried-out by the same species but at different life-stages. As a consequence, population structure affects the balance of inter-specific associations, a topic that is receiving increased attention. In this paper, we developed a model that captures the basic features of the interaction between a flowering plant and an insect with a larval stage that feeds on the plant's vegetative tissues (e.g. leaves and an adult pollinator stage. Our model is able to display a rich set of dynamics, the most remarkable of which involves victim-exploiter oscillations that allow plants to attain abundances above their carrying capacities and the periodic alternation between states dominated by mutualism or antagonism. Our study indicates that changes in the insect's life cycle can modify the balance between mutualism and antagonism, causing important qualitative changes in the interaction dynamics. These changes in the life cycle could be caused by a variety of external drivers, such as temperature, plant nutrients, pesticides and changes in the diet of adult pollinators.

  2. A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity.

    Science.gov (United States)

    Chan, Ying Kai; Gack, Michaela U

    2016-05-01

    14-3-3 proteins regulate biological processes by binding to phosphorylated serine or phosphorylated threonine motifs of cellular proteins. Among the 14-3-3 proteins, 14-3-3ɛ serves a crucial function in antiviral immunity by mediating the cytosol-to-mitochondrial membrane translocation of the pathogen sensor RIG-I. Here we found that the NS3 protein of dengue virus (DV) bound to 14-3-3ɛ and prevented translocation of RIG-I to the adaptor MAVS and thereby blocked antiviral signaling. Intriguingly, a highly conserved phosphomimetic RxEP motif in NS3 was essential for the binding of 14-3-3ɛ. A recombinant mutant DV deficient in binding to 14-3-3ɛ showed impairment in antagonism of RIG-I and elicited a markedly augmented innate immune response and enhanced T cell activation. Our work reveals a novel phosphomimetic-based mechanism for viral antagonism of 14-3-3-mediated immunity, which might guide the rational design of therapeutics. PMID:26998762

  3. Role of sensitive test-cultures in manifestation of antagonism by human symbiotic bacteria

    Directory of Open Access Journals (Sweden)

    Semenov А.V.

    2011-06-01

    Full Text Available Aim. The study considers the influence of sensitive test-cultures on antagonistic activity and production antimicrobial factors by indigenous and probiotic microorganisms. Material. The original method has been used. It is based on determination of survival of sensitive test-culture under the action of cultural liquids of antagonist processed by metabolites and peptidoglycan of sensitive culture. Resalts. The important role of sensitive test-culture in manifestation of the antagonism active microorganisms has been proved. Received data have proved that antagonistic bacterial activity is a result of cross-species interaction between active and sensitive cultures. The effectors are antimicrobial factors and their regulators. The ability of bacterial peptidoglycan to regulate the cross-species interaction between prokaryotes has been firstly shown. Conclusion. The article concludes that the investigation has revealed new mechanisms of colonization resistance of biotope. It has opened prospects of development of principal new probiotic, prebiotic, sinbiotic, biologically active additive and functional products on the basis of microbial stimulators of bacterial antagonism

  4. Anthranilate deteriorates the structure of Pseudomonas aeruginosa biofilms and antagonizes the biofilm-enhancing indole effect.

    Science.gov (United States)

    Kim, Soo-Kyoung; Park, Ha-Young; Lee, Joon-Hee

    2015-04-01

    Anthranilate and indole are alternative degradation products of tryptophan, depending on the bacterial species. While indole enhances the biofilm formation of Pseudomonas aeruginosa, we found that anthranilate, the tryptophan degradation product of P. aeruginosa, had an opposite effect on P. aeruginosa biofilm formation, in which anthranilate deteriorated the mushroom structure of biofilm. The anthranilate effect on biofilm formation was differentially exerted depending on the developmental stage and the presence of shear force. Anthranilate slightly accelerated the initial attachment of P. aeruginosa at the early stage of biofilm development and appeared to build more biofilm without shear force. But anthranilate weakened the biofilm structure in the late stage, deteriorating the mushroom structure of biofilms with shear force to make a flat biofilm. To investigate the interplay of anthranilate with indole in biofilm formation, biofilms were cotreated with anthranilate and indole, and the results showed that anthranilate antagonized the biofilm-enhancing effect of indole. Anthranilate was able to deteriorate the preformed biofilm. The effect of anthranilate and indole on biofilm formation was quorum sensing independent. AntR, a regulator of anthranilate-degrading metabolism was synergistically activated by cotreatment with anthranilate and indole, suggesting that indole might enhance biofilm formation by facilitating the degradation of anthranilate. Anthranilate slightly but significantly affected the cyclic diguaniylate (c-di-GMP) level and transcription of major extracellular polysaccharide (Psl, Pel, and alginate) operons. These results suggest that anthranilate may be a promising antibiofilm agent and antagonize the effect of indole on P. aeruginosa biofilm formation.

  5. Antagonism of Trichoderma harzianum ETS 323 on Botrytis cinerea mycelium in culture conditions.

    Science.gov (United States)

    Cheng, Chi-Hua; Yang, Chia-Ann; Peng, Kou-Cheng

    2012-11-01

    ABSTRACT Previous studies have shown that the extracellular proteins of Trichoderma harzianum ETS 323 grown in the presence of deactivated Botrytis cinerea in culture include a putative l-amino acid oxidase and have suggested the involvement of this enzyme in the antagonistic mechanism. Here, we hypothesized that the mycoparasitic process of Trichoderma spp. against B. cinerea involves two steps; that is, an initial hyphal coiling stage and a subsequent hyphal coiling stage, with different coiling rates. The two-step antagonism of T. harzianum ETS 323 against B. cinerea during the mycoparasitic process in culture was evaluated using a biexponential equation. In addition, an l-amino acid oxidase (Th-l-AAO) was identified from T. harzianum ETS 323. The secretion of Th-l-AAO was increased when T. harzianum ETS 323 was grown with deactivated hyphae of B. cinerea. Moreover, in vitro assays indicated that Th-l-AAO effectively inhibited B. cinerea hyphal growth, caused cytosolic vacuolization in the hyphae, and led to hyphal lysis. Th-l-AAO also showed disease control against the development of B. cinerea on postharvest apple fruit and tobacco leaves. Furthermore, an apoptosis-like response, including the generation of reactive oxygen species, was observed in B. cinerea after treatment with Th-l-AAO, suggesting that Th-l-AAO triggers programmed cell death in B. cinerea. This may be associated with the two-step antagonism of T. harzianum ETS 323 against B. cinerea.

  6. Basis for antagonism by sodium bentazon of tritosulfuron toxicity to white bean (Phaseolus vulgaris L.).

    Science.gov (United States)

    Weinberg, Tsafrir; Stephenson, Gerald R; McLean, Michael D; Satchivi, Norbert M; Hall, J Christopher

    2007-03-21

    White bean (Phaseolus vulgaris L.) was used to study the antagonism caused by Na-bentazon on the phytotoxic action of the sulfonylurea (SU) herbicide tritosulfuron. After 168 h, uptake and translocation of [14C]tritosulfuron were reduced by 60 and 89%, respectively, when Na-bentazon was added to the mixture. Addition of (NH4)2SO4 or replacement of Na-bentazon with NH4-bentazon completely eliminated the negative effects on [14C]tritosulfuron uptake but not on its translocation. Scanning electron microscopy revealed that a mixture of Na-bentazon plus tritosulfuron plus DASH HC (0.156%) formed a rough layer of grain-like crystals on the leaf surface, whereas the addition of (NH4)2SO4 or replacement of Na-bentazon with NH4-bentazon resulted in amorphous deposits that may be more easily absorbed. The antagonism of tritosulfuron's phytotoxicity by Na-bentazon involves two separate processes, chemical (uptake effect) and biochemical (translocation effect). PMID:17311398

  7. Microwave facilitation of domperidone antagonism of apomorphine-induced stereotypic climbing in mice

    Energy Technology Data Exchange (ETDEWEB)

    Quock, R.M.; Kouchich, F.J.; Ishii, T.K.; Lange, D.G.

    1987-01-01

    The dopaminergic agonist apomorphine produced dose-dependent stereotypic climbing behavior in mice housed in cages with vertical bars. This drug effect was competitively inhibited by systemic pretreatment with the centrally acting dopaminergic antagonist haloperidol but not by microwave irradiation (2.45 GHz, 20 mW/cm2, CW, 10 min) nor by systemic pretreatment with domperidone, a dopaminergic antagonist that only poorly penetrates the blood-brain barrier (BBB). Yet when mice were systemically pretreated with domperidone and then subjected to microwave irradiation (as above), the apomorphine effect was significantly reduced. Microwave irradiation also facilitated antagonism of the apomorphine effect by low and otherwise ineffective systemic pretreatment doses of haloperidol. Apomorphine-induced stereotypic climbing behavior was also reduced by domperidone administered intracerebrally, which bypassed the BBB. Exposure of intracerebral domperidone-pretreated animals to microwave irradiation failed to increase the degree of antagonism. These findings indicate that microwave irradiation can facilitate central effects of domperidone, a drug which acts mainly in the periphery. One possible explanation for these findings is that microwave irradiation alters the permeability of the BBB and increases the entry of domperidone to central sites of action.

  8. FCJ-156 Hacking the Social: Internet Memes, Identity Antagonism, and the Logic of Lulz.

    Directory of Open Access Journals (Sweden)

    Ryan M. Milner

    2013-12-01

    Full Text Available 4chan and reddit are participatory media collectives undergirded by a “logic of lulz” that favours distanced irony and critique. It often works at the expense of core identity categories like race and gender. However, the logic need not be entirely counterproductive to public discourse. Provided that diverse identities find voice instead of exclusion, these sites may facilitate vibrant, agonistic discussion instead of disenfranchising antagonism. In order to assess this potential for productive agonism, I undertook a critical discourse analysis of these collectives. Emphasising the image memes they produce, I evaluated discourses on race and gender. Both race and gender representations were dominated by familiar stereotypes and partial representations. However, while dissenting perspectives on race were repressed or excluded, dissenting perspectives on gender were vocalised and contested. The ‘logic of lulz’ facilitated both dominance and counter, each articulated with heavy reliance on irony and critique. This logic ambiguously balanced agonism and antagonism, but contestation provided sharper engagement than repression.

  9. IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein

    Directory of Open Access Journals (Sweden)

    Jingyou Yu

    2015-10-01

    Full Text Available The interferon-induced transmembrane (IFITM proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env, thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection.

  10. Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Daisy W.; Prins, Kathleen C.; Borek, Dominika M.; Farahbakhsh, Mina; Tufariello, JoAnn M.; Ramanan, Parameshwaran; Nix, Jay C.; Helgeson, Luke A.; Otwinowski, Zbyszek; Honzatko, Richard B.; Basler, Christopher F.; Amarasinghe, Gaya K. (Sinai); (Iowa State); (LBNL); (UTSMC)

    2010-03-12

    Ebola viral protein 35 (VP35), encoded by the highly pathogenic Ebola virus, facilitates host immune evasion by antagonizing antiviral signaling pathways, including those initiated by RIG-I-like receptors. Here we report the crystal structure of the Ebola VP35 interferon inhibitory domain (IID) bound to short double-stranded RNA (dsRNA), which together with in vivo results reveals how VP35-dsRNA interactions contribute to immune evasion. Conserved basic residues in VP35 IID recognize the dsRNA backbone, whereas the dsRNA blunt ends are 'end-capped' by a pocket of hydrophobic residues that mimic RIG-I-like receptor recognition of blunt-end dsRNA. Residues critical for RNA binding are also important for interferon inhibition in vivo but not for viral polymerase cofactor function of VP35. These results suggest that simultaneous recognition of dsRNA backbone and blunt ends provides a mechanism by which Ebola VP35 antagonizes host dsRNA sensors and immune responses.

  11. Aggression, Sibling Antagonism, and Theory of Mind During the First Year of Siblinghood: A Developmental Cascade Model.

    Science.gov (United States)

    Song, Ju-Hyun; Volling, Brenda L; Lane, Jonathan D; Wellman, Henry M

    2016-07-01

    A developmental cascade model was tested to examine longitudinal associations among firstborn children's aggression, theory of mind (ToM), and antagonism toward their younger sibling during the 1st year of siblinghood. Aggression and ToM were assessed before the birth of a sibling and 4 and 12 months after the birth, and antagonism was examined at 4 and 12 months in a sample of 208 firstborn children (initial Mage  = 30 months, 56% girls) from primarily European American, middle-class families. Firstborns' aggression consistently predicted high sibling antagonism both directly and through poorer ToM. Results highlight the importance of examining longitudinal influences across behavioral, social-cognitive, and relational factors that are closely intertwined even from the early years of life.

  12. Plant responses against invasive nucleic acids: RNA silencing and its suppression by plant viral pathogens

    OpenAIRE

    Alvarado, Veria; Herman B Scholthof

    2009-01-01

    RNA silencing is a common strategy shared by eukaryotic organisms to regulate gene expression, and also operates as a defense mechanism against invasive nucleic acids such as viral transcripts. The silencing pathway is quite sophisticated in higher eukaryotes but the distinct steps and nature of effector complexes vary between and even within species. To counteract this defense mechanism viruses have evolved the ability to encode proteins that suppress silencing to protect their genomes from ...

  13. Characteristics of RNA silencing in plants: similarities and differences across kingdoms.

    Science.gov (United States)

    Susi, P; Hohkuri, M; Wahlroos, T; Kilby, N J

    2004-01-01

    RNA silencing is a collective term that encompasses the sequence of events that leads to the targeted degradation of cellular mRNA and thus to the silencing of corresponding gene expression. RNA silencing is initiated after introduction into the host genome of a gene that is homologous to an endogenous gene. Transcription of the introduced gene results in the formation of double-stranded RNA (dsRNA) that is cut into smaller dsRNA species termed small interfering RNAs (siRNAs) by an RNaseIII-like enzyme called 'Dicer'. siRNAs associate with a protein complex termed the 'RNA-induced silencing complex' (RISC), which mediates the binding of one strand of siRNAs with mRNAs transcribed from the native 'target' gene. The binding of siRNAs with native gene mRNAs earmarks native gene mRNAs for destruction, resulting in gene silencing. In plants, RNA silencing appears to serve as a defence mechanism against viral pathogens and also to suppress the activity of virus-like mobile genetic elements. In an apparent response to RNA silencing, some plant viruses express suppressors of RNA silencing. RNA silencing also is directly implicated in the regulation of the function(s) of microRNAs, which are the key determinants in an additional cellular mechanism related to the translational repression of genes, the effect of which ultimately impinges on development. The high degree of sequence similarity that exists between genes involved in RNA silencing in widely different organisms underscores the conserved nature of many aspects of the RNA silencing mechanism. However, depending (for example) on the precise nature of the target gene involved, there also are significant differences in the silencing pathways that are engaged by various organisms.

  14. Alfalfa dwarf cytorhabdovirus P protein is a local and systemic RNA silencing supressor which inhibits programmed RISC activity and prevents transitive amplification of RNA silencing.

    Science.gov (United States)

    Bejerman, Nicolás; Mann, Krin S; Dietzgen, Ralf G

    2016-09-15

    Plants employ RNA silencing as an innate defense mechanism against viruses. As a counter-defense, plant viruses have evolved to express RNA silencing suppressor proteins (RSS), which target one or more steps of the silencing pathway. In this study, we show that the phosphoprotein (P) encoded by the negative-sense RNA virus alfalfa dwarf virus (ADV), a species of the genus Cytorhabdovirus, family Rhabdoviridae, is a suppressor of RNA silencing. ADV P has a relatively weak local RSS activity, and does not prevent siRNA accumulation. On the other hand, ADV P strongly suppresses systemic RNA silencing, but does not interfere with the short-distance spread of silencing, which is consistent with its lack of inhibition of siRNA accumulation. The mechanism of suppression appears to involve ADV P binding to RNA-induced silencing complex proteins AGO1 and AGO4 as shown in protein-protein interaction assays when ectopically expressed. In planta, we demonstrate that ADV P likely functions by inhibiting miRNA-guided AGO1 cleavage and prevents transitive amplification by repressing the production of secondary siRNAs. As recently described for lettuce necrotic yellows cytorhabdovirus P, but in contrast to other viral RSS known to disrupt AGO activity, ADV P sequence does not contain any recognizable GW/WG or F-box motifs, which suggests that cytorhabdovirus P proteins may use alternative motifs to bind to AGO proteins. PMID:27543392

  15. Inhibition of protein synthesis does not antagonize induction of UV-induced sister-chromatid exchange in xeroderma pigmentosum cells

    International Nuclear Information System (INIS)

    Cycloheximide strongly antagonizes the induction of sisterchromatid exchanges by ethyl methanesulfonate or mitomycin C in human skin fibroblast and xeroderma pigmentosum cells (group A). Analogous behavior has been observed in several other species including Chinese hamster and plant cells. This report documents an exception to that pattern: cycloheximide fails to antagonize UV-induced sister chromatid exchange in xeroderma pigmentosum cells, whereas it does in normal human skin fibroblast cells. A genetic defect in these cells is postulated to alter the UV-mediated DNA recombination process. (author)

  16. Exon silencing by UAGG motifs in response to neuronal excitation.

    Directory of Open Access Journals (Sweden)

    Ping An

    2007-02-01

    Full Text Available Alternative pre-mRNA splicing plays fundamental roles in neurons by generating functional diversity in proteins associated with the communication and connectivity of the synapse. The CI cassette of the NMDA R1 receptor is one of a variety of exons that show an increase in exon skipping in response to cell excitation, but the molecular nature of this splicing responsiveness is not yet understood. Here we investigate the molecular basis for the induced changes in splicing of the CI cassette exon in primary rat cortical cultures in response to KCl-induced depolarization using an expression assay with a tight neuron-specific readout. In this system, exon silencing in response to neuronal excitation was mediated by multiple UAGG-type silencing motifs, and transfer of the motifs to a constitutive exon conferred a similar responsiveness by gain of function. Biochemical analysis of protein binding to UAGG motifs in extracts prepared from treated and mock-treated cortical cultures showed an increase in nuclear hnRNP A1-RNA binding activity in parallel with excitation. Evidence for the role of the NMDA receptor and calcium signaling in the induced splicing response was shown by the use of specific antagonists, as well as cell-permeable inhibitors of signaling pathways. Finally, a wider role for exon-skipping responsiveness is shown to involve additional exons with UAGG-related silencing motifs, and transcripts involved in synaptic functions. These results suggest that, at the post-transcriptional level, excitable exons such as the CI cassette may be involved in strategies by which neurons mount adaptive responses to hyperstimulation.

  17. Chemogenetic silencing of neurons in retrosplenial cortex disrupts sensory preconditioning.

    Science.gov (United States)

    Robinson, Siobhan; Todd, Travis P; Pasternak, Anna R; Luikart, Bryan W; Skelton, Patrick D; Urban, Daniel J; Bucci, David J

    2014-08-13

    An essential aspect of episodic memory is the formation of associations between neutral sensory cues in the environment. In light of recent evidence that this critical aspect of learning does not require the hippocampus, we tested the involvement of the retrosplenial cortex (RSC) in this process using a chemogenetic approach that allowed us to temporarily silence neurons along the entire rostrocaudal extent of the RSC. A viral vector containing the gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) was infused into RSC. When the receptor was later activated by systemic injection of clozapine-N-oxide, neural activity in RSC was transiently silenced (confirmed using a patch-clamp procedure). Rats expressing hM4Di and control rats were trained in a sensory preconditioning procedure in which a tone and light were paired on some trials and a white noise stimulus was presented alone on the other trials during the Preconditioning phase. Thus, rats were given the opportunity to form an association between a tone and a light in the absence of reinforcement. Later, the light was paired with food. During the test phase when the auditory cues were presented alone, controls exhibited more conditioned responding during presentation of the tone compared with the white noise reflecting the prior formation of a tone-light association. Silencing RSC neurons during the Preconditioning phase prevented the formation of an association between the tone and light and eliminated the sensory preconditioning effect. These findings indicate that RSC may contribute to episodic memory formation by linking essential sensory stimuli during learning.

  18. Breaking the Silence in The Global Public Sphere

    OpenAIRE

    Madsen, Marianne Mosegaard; Sørensen, Line Toft

    2014-01-01

    The aim of this project has been to examine to what extent a social movement like Breaking the Silence can position itself within the global public sphere and further how it then can use times position to create awareness and gain momentum in the Israeli public sphere. This has been done through the use of two theoretical frameworks, one focusing on the global public sphere and one focusing on farming theory. In order to connect these two theoretical frameworks we chose to use injustice frami...

  19. Sounds of silence%沉默的声音

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Four monks decided to meditate1 silently without speaking for two weeks. By nightfall on the first day,the candle began to flicker and then went out.The first monk said,"Oh, no!The candle is out."The second monk said,"Aren't we not supposed to talk?"The third monk said, "Why must you two break the silence?"The fourth monk laughed and said, "Ha! I'm the only one who didn't speak."

  20. CAPN5 gene silencing by short hairpin RNA interference

    OpenAIRE

    Nelson, Nnamdi G; Jessica M Skeie; Muradov, Hakim; Rowell, Hannah A; Seo, Seongjin; Mahajan, Vinit B

    2014-01-01

    Background The purpose of this project was to identify short hairpin RNA (shRNA) sequences that can suppress expression of human CAPN5 in which gain-of-function mutants cause autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). We created HEK293T cells that stably express an ADNIV disease allele, CAPN5-p.R243L. Transfection protocols were optimized for neuroblastoma SHSY5Y cells. The gene silencing effect of four different shRNA plasmids that target CAPN5 was tested. RNA and...

  1. Automatic Identification of Silence, Unvoiced and Voiced Chunks in Speech

    Directory of Open Access Journals (Sweden)

    Poonam Sharma

    2013-05-01

    Full Text Available The objective of this work is to automatically seg ment the speech signal into silence, voiced and unvoiced regions which are very beneficial in incre asing the accuracy and performance of recognition systems. Proposed algorithm is based on three important characteristics of speech signal namely Zero Crossing Rate, Short Time Energy and Fundamental Frequency. The performance of the proposed algorithm is evaluated using the data collected from four different speakers and an overall accuracy of 96.61 % is achi eved.

  2. LINEing germ and embryonic stem cells' silencing of retrotransposons.

    Science.gov (United States)

    Ishiuchi, Takashi; Torres-Padilla, Maria-Elena

    2014-07-01

    Almost half of our genome is occupied by transposable elements. Although most of them are inactive, one type of non-long terminal repeat (LTR) retrotransposon, long interspersed nuclear element 1 (LINE1), is capable of retrotransposition. Two studies in this issue, Pezic and colleagues (pp. 1410-1428) and Castro-Diaz and colleagues (pp. 1397-1409), provide novel insight into the regulation of LINE1s in human embryonic stem cells and mouse germ cells and shed new light on the conservation of complex mechanisms to ensure silencing of transposable elements in mammals.

  3. Tobacco mosaic virus movement protein enhances the spread of RNA silencing.

    Directory of Open Access Journals (Sweden)

    Hannes Vogler

    2008-04-01

    Full Text Available Eukaryotic cells restrain the activity of foreign genetic elements, including viruses, through RNA silencing. Although viruses encode suppressors of silencing to support their propagation, viruses may also exploit silencing to regulate host gene expression or to control the level of their accumulation and thus to reduce damage to the host. RNA silencing in plants propagates from cell to cell and systemically via a sequence-specific signal. Since the signal spreads between cells through plasmodesmata like the viruses themselves, virus-encoded plasmodesmata-manipulating movement proteins (MP may have a central role in compatible virus:host interactions by suppressing or enhancing the spread of the signal. Here, we have addressed the propagation of GFP silencing in the presence and absence of MP and MP mutants. We show that the protein enhances the spread of silencing. Small RNA analysis indicates that MP does not enhance the silencing pathway but rather enhances the transport of the signal through plasmodesmata. The ability to enhance the spread of silencing is maintained by certain MP mutants that can move between cells but which have defects in subcellular localization and do not support the spread of viral RNA. Using MP expressing and non-expressing virus mutants with a disabled silencing suppressing function, we provide evidence indicating that viral MP contributes to anti-viral silencing during infection. Our results suggest a role of MP in controlling virus propagation in the infected host by supporting the spread of silencing signal. This activity of MP involves only a subset of its properties implicated in the spread of viral RNA.

  4. An effective silencer design for artificially air conditioned environment.

    Science.gov (United States)

    Fujiwara, Kyoji; Pang, Li Feng

    2004-11-01

    An effective silencer for an air conditioning duct is studied. A duct with an acoustically soft boundary is employed as an effective silencer. On the acoustically soft boundary the sound pressure is zero and it is impossible to realize such boundary in the air-borne sound field, because of the non-existence of a much lighter medium than the air. In this study, the arrangement of one-quarter wave-length acoustic tubes is employed as a soft boundary. This acoustic tube has frequency dependence, but the sound pressure becomes nearly zero at the tube mouth around the odd resonance frequency. The relation between the noise reduction efficiency and this acoustically soft boundary is examined experimentally and more than 40 dB noise reduction is obtained in a one-half octave band around the first resonance frequency. It is also made clear that more than one wave length of soft boundary is required to get enough reduction compared with the reduction obtained in the case of quite a long soft boundary.

  5. Efficient Virus-Induced Gene Silencing in Solanum rostratum

    Science.gov (United States)

    Meng, Lan-Huan; Wang, Rui-Heng; Zhu, Ben-Zhong; Zhu, Hong-Liang; Luo, Yun-Bo; Fu, Da-Qi

    2016-01-01

    Solanum rostratum is a “super weed” that grows fast, is widespread, and produces the toxin solanine, which is harmful to both humans and other animals. To our knowledge, no study has focused on its molecular biology owing to the lack of available transgenic methods and sequence information for S. rostratum. Virus-induced gene silencing (VIGS) is a powerful tool for the study of gene function in plants; therefore, in the present study, we aimed to establish tobacco rattle virus (TRV)-derived VIGS in S. rostratum. The genes for phytoene desaturase (PDS) and Chlorophyll H subunit (ChlH) of magnesium protoporphyrin chelatase were cloned from S. rostratum and used as reporters of gene silencing. It was shown that high-efficiency VIGS can be achieved in the leaves, flowers, and fruit of S. rostratum. Moreover, based on our comparison of three different types of infection methods, true leaf infection was found to be more efficient than cotyledon and sprout infiltration in long-term VIGS in multiple plant organs. In conclusion, the VIGS technology and tomato genomic sequences can be used in the future to study gene function in S. rostratum. PMID:27258320

  6. Efficient Virus-Induced Gene Silencing in Solanum rostratum.

    Directory of Open Access Journals (Sweden)

    Lan-Huan Meng

    Full Text Available Solanum rostratum is a "super weed" that grows fast, is widespread, and produces the toxin solanine, which is harmful to both humans and other animals. To our knowledge, no study has focused on its molecular biology owing to the lack of available transgenic methods and sequence information for S. rostratum. Virus-induced gene silencing (VIGS is a powerful tool for the study of gene function in plants; therefore, in the present study, we aimed to establish tobacco rattle virus (TRV-derived VIGS in S. rostratum. The genes for phytoene desaturase (PDS and Chlorophyll H subunit (ChlH of magnesium protoporphyrin chelatase were cloned from S. rostratum and used as reporters of gene silencing. It was shown that high-efficiency VIGS can be achieved in the leaves, flowers, and fruit of S. rostratum. Moreover, based on our comparison of three different types of infection methods, true leaf infection was found to be more efficient than cotyledon and sprout infiltration in long-term VIGS in multiple plant organs. In conclusion, the VIGS technology and tomato genomic sequences can be used in the future to study gene function in S. rostratum.

  7. Efficient Virus-Induced Gene Silencing in Solanum rostratum.

    Science.gov (United States)

    Meng, Lan-Huan; Wang, Rui-Heng; Zhu, Ben-Zhong; Zhu, Hong-Liang; Luo, Yun-Bo; Fu, Da-Qi

    2016-01-01

    Solanum rostratum is a "super weed" that grows fast, is widespread, and produces the toxin solanine, which is harmful to both humans and other animals. To our knowledge, no study has focused on its molecular biology owing to the lack of available transgenic methods and sequence information for S. rostratum. Virus-induced gene silencing (VIGS) is a powerful tool for the study of gene function in plants; therefore, in the present study, we aimed to establish tobacco rattle virus (TRV)-derived VIGS in S. rostratum. The genes for phytoene desaturase (PDS) and Chlorophyll H subunit (ChlH) of magnesium protoporphyrin chelatase were cloned from S. rostratum and used as reporters of gene silencing. It was shown that high-efficiency VIGS can be achieved in the leaves, flowers, and fruit of S. rostratum. Moreover, based on our comparison of three different types of infection methods, true leaf infection was found to be more efficient than cotyledon and sprout infiltration in long-term VIGS in multiple plant organs. In conclusion, the VIGS technology and tomato genomic sequences can be used in the future to study gene function in S. rostratum.

  8. ABCE1 is a highly conserved RNA silencing suppressor.

    Directory of Open Access Journals (Sweden)

    Kairi Kärblane

    Full Text Available ATP-binding cassette sub-family E member 1 (ABCE1 is a highly conserved protein among eukaryotes and archaea. Recent studies have identified ABCE1 as a ribosome-recycling factor important for translation termination in mammalian cells, yeast and also archaea. Here we report another conserved function of ABCE1. We have previously described AtRLI2, the homolog of ABCE1 in the plant Arabidopsis thaliana, as an endogenous suppressor of RNA silencing. In this study we show that this function is conserved: human ABCE1 is able to suppress RNA silencing in Nicotiana benthamiana plants, in mammalian HEK293 cells and in the worm Caenorhabditis elegans. Using co-immunoprecipitation and mass spectrometry, we found a number of potential ABCE1-interacting proteins that might support its function as an endogenous suppressor of RNA interference. The interactor candidates are associated with epigenetic regulation, transcription, RNA processing and mRNA surveillance. In addition, one of the identified proteins is translin, which together with its binding partner TRAX supports RNA interference.

  9. Evaluation of BACE1 Silencing in Cellular Models

    Directory of Open Access Journals (Sweden)

    Malgorzata Sierant

    2009-01-01

    Full Text Available Beta-secretase (BACE1 is the major enzyme participating in generation of toxic amyloid-beta (Aβ peptides, identified in amyloid plaques of Alzheimer's disease (AD brains. Its downregulation results in decreasing secretion of Aβ. Thus, BACE1 silencing by RNAi represents possible strategy for antiamyloid therapy in the treatment of AD. In this study, a series of newly designed sequences of synthetic and vector-encoded siRNAs (pSilencer, pcPURhU6, and lentivirus were tested against overexpressed and endogenous BACE1 in several cell lines and in adult neural progenitor cells, derived from rat hippocampus. SiRNAs active in human, mouse, and rat cell models were shown to diminish the level of BACE1. In HCN A94 cells, two BACE1-specific siRNAs did not alter the expression of genes of BACE2 and several selected genes involved in neurogenesis (Synapsin I, βIII-Tubulin, Calbidin, NeuroD1, GluR2, CREB, MeCP2, PKR, however, remarkable lowering of SCG10 mRNA, coding protein of stathmin family, important in the development of nervous system, was observed.

  10. Gene silencing by RNAi in mouse Sertoli cells

    Directory of Open Access Journals (Sweden)

    del Mazo Jesús

    2008-07-01

    Full Text Available Abstract Background RNA interference (RNAi is a valuable tool in the investigation of gene function. The purpose of this study was to examine the availability, target cell types and efficiency of RNAi in the mouse seminiferous epithelium. Methods The experimental model was based on transgenic mice expressing EGFP (enhanced green fluorescent protein. RNAi was induced by in vivo transfection of plasmid vectors encoding for short hairpin RNAs (shRNAs targeting EGFP. shRNAs were transfected in vivo by microinjection into the seminiferous tubules via the rete testis followed by square wave electroporation. As a transfection reporter, expression of red fluorescent protein (HcRed 1 was used. Cell types, the efficiency of both transfections and RNAi were all evaluated. Results Sertoli cells were the main transfected cells. A reduction of about 40% in the level of EGFP protein was detected in cells successfully transfected both in vivo and in vitro. However, the efficiency of in vivo transfection was low. Conclusion In adult seminiferous epithelial cells, in vivo post-transcriptional gene silencing mediated by RNAi via shRNA is efficient in Sertoli cells. Similar levels of RNAi were detected both in vivo and in vitro. This also indicates that Sertoli cells have the necessary silencing machinery to repress the expression of endogenous genes via RNAi.

  11. Epigeneitc silencing of ribosomal RNA genes by Mybbp1a

    Directory of Open Access Journals (Sweden)

    Tan Bertrand

    2012-06-01

    Full Text Available Abstract Background Transcription of the ribosomal RNA gene repeats by Pol I occurs in the nucleolus and is a fundamental step in ribosome biogenesis and protein translation. Due to tight coordination between ribosome biogenesis and cell proliferation, transcription of rRNA and stable maintenance of rDNA clusters are thought to be under intricate control by intercalated mechanisms, particularly at the epigenetic level. Methods and Results Here we identify the nucleolar protein Myb-binding protein 1a (Mybbp1a as a novel negative regulator of rRNA expression. Suppression of rDNA transcription by Mybbp1a was linked to promoter regulation as illustrated by its binding to the chromatin around the hypermethylated, inactive rDNA gene promoters. Our data further showed that downregulation of Mybbp1a abrogated the local DNA methylation levels and histone marks associated with gene silencing, and altered the promoter occupancy of various factors such UBF and HDACs, consequently leading to elevated rRNA expression. Mechanistically, we propose that Mybbp1a maintains rDNA repeats in a silenced state while in association with the negative epigenetic modifiers HDAC1/2. Conclusions Results from our present work reveal a previously unrecognized co-repressor role of Mybbp1a in rRNA expression. They are further consistent with the scenario that Mybbp1a is an integral constituent of the rDNA epigenetic regulation that underlies the balanced state of rDNA clusters.

  12. Sexuality and 'silence' among Khasi youth of Meghalaya, Northeast India.

    Science.gov (United States)

    War, Ryntihlin Jennifer; Albert, Sandra

    2013-01-01

    The importance of sex education has been well documented in the literature, but there exists a lack of research involving indigenous youth in India. This paper describes perceptions, knowledge and attitudes towards sex education, sexuality, pre-marital sex, rape and homosexuality among indigenous students from the matrilineal Khasi tribe attending a university in Meghalaya in northeast India. Qualitative and quantitative data were collected during and after reproductive health, sexuality and life skills courses. Despite the impression of sexual permissiveness of indigenous peoples that exists in India, students reported a societal silence on issues related to sexuality. Lack of appropriate words in the indigenous language potentially contributes to this silence. Although co-habitation is common and culturally acceptable, students disapproved of pre-marital sex. The influence of Christianisation was also perceived in the frequent reference to sin and guilt associated with masturbation, homosexuality, pre-marital sex and abortion. Students reported that the sex education received in school was 'childish' and inadequate for their adult needs. Many had unrealistic images of what constituted 'normal' sex and also blamed women for rape. The majority of indigenous students expressed the need for non-judgmental fora for discussions on sexual health and for sexuality education.

  13. Sexuality and 'silence' among Khasi youth of Meghalaya, Northeast India.

    Science.gov (United States)

    War, Ryntihlin Jennifer; Albert, Sandra

    2013-01-01

    The importance of sex education has been well documented in the literature, but there exists a lack of research involving indigenous youth in India. This paper describes perceptions, knowledge and attitudes towards sex education, sexuality, pre-marital sex, rape and homosexuality among indigenous students from the matrilineal Khasi tribe attending a university in Meghalaya in northeast India. Qualitative and quantitative data were collected during and after reproductive health, sexuality and life skills courses. Despite the impression of sexual permissiveness of indigenous peoples that exists in India, students reported a societal silence on issues related to sexuality. Lack of appropriate words in the indigenous language potentially contributes to this silence. Although co-habitation is common and culturally acceptable, students disapproved of pre-marital sex. The influence of Christianisation was also perceived in the frequent reference to sin and guilt associated with masturbation, homosexuality, pre-marital sex and abortion. Students reported that the sex education received in school was 'childish' and inadequate for their adult needs. Many had unrealistic images of what constituted 'normal' sex and also blamed women for rape. The majority of indigenous students expressed the need for non-judgmental fora for discussions on sexual health and for sexuality education. PMID:23758496

  14. Understanding sex determination in the mouse: genetics, epigenetics and the story of mutual antagonisms

    Indian Academy of Sciences (India)

    Andy Greenfield

    2015-12-01

    Recent years have seen a rapid growth in mouse genetics resources that support research into fundamental mechanisms in organogenesis, including those controlling mammalian sex determinations. Numerous mouse mutants have shed light on molecular pathways of cell fate specification during gonadogenesis and the `decision' as to whether testis or ovary development is achieved. These studies indicate substantial genetic complexity, characterized by redundancy, feedback loops, mutual antagonism between testis-determining and ovary-determining gene regulatory networks and a degree of plasticity in the fully differentiated state of the adult gonad that was not appreciated until conditional loss-of-function studies were performed. One challenge now is to understand how controlled epigenomic changes effect the now familiar sexually dimorphic transcriptomic profiles of the male and female gonads, firstly during primary sex determination, but also in the adult gonad, thereby regulating cellular behaviour during morphogenesis and maintaining the differentiated state.

  15. USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

    Directory of Open Access Journals (Sweden)

    Zhenghong Lin

    2013-12-01

    Full Text Available The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  16. O-GlcNAcylation Antagonizes Phosphorylation of CDH1 (CDC20 Homologue 1).

    Science.gov (United States)

    Tian, Jie; Geng, Qizhi; Ding, Yuehe; Liao, Ji; Dong, Meng-Qiu; Xu, Xingzhi; Li, Jing

    2016-06-01

    The anaphase promoting complex/cyclosome (APC/C) orchestrates various aspects of the eukaryotic cell cycle. One of its co-activators, Cdh1, is subject to myriad post-translational modifications, such as phosphorylation and ubiquitination. Herein we identify the O-linked N-acetylglucosamine (O-GlcNAc) modification that occurs on Cdh1. Cdh1 is O-GlcNAcylated in cultured cells and mouse brain extracts. Mass spectrometry identifies an O-GlcNAcylated peptide that neighbors a known phosphorylation site. Cell synchronization and mutation studies reveal that O-GlcNAcylation of Cdh1 may antagonize its phosphorylation. Our results thus reveal a pivotal role of O-GlcNAcylation in regulating APC/C activity.

  17. Combining climate and energy policies: synergies or antagonism? Modeling interactions with energy efficiency instruments

    International Nuclear Information System (INIS)

    In addition to the already present Climate and Energy package, the European Union (EU) plans to include a binding target to reduce energy consumption. We analyze the rationales the EU invokes to justify such an overlapping and develop a minimal common framework to study interactions arising from the combination of instruments reducing emissions, promoting renewable energy (RE) production and reducing energy demand through energy efficiency (EE) investments. We find that although all instruments tend to reduce GHG emissions and although a price on carbon tends also to give the right incentives for RE and EE, the combination of more than one instrument leads to significant antagonisms regarding major objectives of the policy package. The model allows to show in a single framework and to quantify the antagonistic effects of the joint promotion of RE and EE. We also show and quantify the effects of this joint promotion on ETS permit price, on wholesale market price and on energy production levels. (authors)

  18. Tetrahydro-iso-alpha Acids Antagonize Estrogen Receptor Alpha Activity in MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maëlle Lempereur

    2016-01-01

    Full Text Available Tetrahydro-iso-alpha acids commonly called THIAA or Tetra are modified hop acids extracted from hop (Humulus lupulus L. which are frequently used in brewing industry mainly in order to provide beer bitterness and foam stability. Interestingly, molecular structure of tetrahydro-iso-alpha acids is close to a new type of estrogen receptor alpha (ERα antagonists aimed at disrupting the binding of coactivators containing an LxxLL motif (NR-box. In this work we show that THIAA decreases estradiol-stimulated proliferation of MCF-7 (ERα-positive breast cancer cells. Besides, we show that it inhibits ERα transcriptional activity. Interestingly, this extract fails to compete with estradiol for ERα binding and does not significantly impact the receptor turnover rate in MCF-7 cells, suggesting that it does not act like classical antiestrogens. Hence, we demonstrate that THIAA is able to antagonize ERα estradiol-induced recruitment of the LxxLL binding motif.

  19. Tetrahydro-iso-alpha Acids Antagonize Estrogen Receptor Alpha Activity in MCF-7 Breast Cancer Cells.

    Science.gov (United States)

    Lempereur, Maëlle; Majewska, Claire; Brunquers, Amandine; Wongpramud, Sumalee; Valet, Bénédicte; Janssens, Philippe; Dillemans, Monique; Van Nedervelde, Laurence; Gallo, Dominique

    2016-01-01

    Tetrahydro-iso-alpha acids commonly called THIAA or Tetra are modified hop acids extracted from hop (Humulus lupulus L.) which are frequently used in brewing industry mainly in order to provide beer bitterness and foam stability. Interestingly, molecular structure of tetrahydro-iso-alpha acids is close to a new type of estrogen receptor alpha (ERα) antagonists aimed at disrupting the binding of coactivators containing an LxxLL motif (NR-box). In this work we show that THIAA decreases estradiol-stimulated proliferation of MCF-7 (ERα-positive breast cancer cells). Besides, we show that it inhibits ERα transcriptional activity. Interestingly, this extract fails to compete with estradiol for ERα binding and does not significantly impact the receptor turnover rate in MCF-7 cells, suggesting that it does not act like classical antiestrogens. Hence, we demonstrate that THIAA is able to antagonize ERα estradiol-induced recruitment of the LxxLL binding motif. PMID:27190515

  20. The absence of antagonism between extracts of Clinacanthus nutans Burm. and Naja naja siamensis venom.

    Science.gov (United States)

    Cherdchu, C; Poopyruchpong, N; Adchariyasucha, R; Ratanabanangkoon, K

    1977-06-01

    Clinacanthus nutans Burm, a herb reputed in Thailand and Malaysia to be "snakebite antidote" has been tested in vitro and in vivo for antivenin activity. The aqueous extract of C. nutans leaves has been found to have no effect on the inhibition of neuromuscular transmission produced by purified Naja naja siamensis neurotoxin in isolated rat phrenic-nerve diaphragm preparations. The extract of C. nutans, when given orally or intraperitoneally, are ineffective in prolonging the survival time of experimental mice receiving lethal doses of N.n. siamensis crude venom. Oral administrations of the herb extracts pretreated with alpha-amylase or beta-amylase also fail to protect the animal. It is concluded that the extract of C. nutans can not antagonize the action of cobra venom. PMID:199949

  1. Puerarin antagonizes peroxyntrite-induced injury in retinal pigment epithelial cells

    Institute of Scientific and Technical Information of China (English)

    Lina Hao; Xudong Zhang; Tao Yang; Junling Ma

    2012-01-01

    A rat model of diabetes mellitus was established by intraperitoneal injection of streptozotocin. Three days later, the rats were intraperitoneally administered 140 mg puerarin/kg daily, for a total of 60 successive days. DNA ladder results showed increased apoptosis over time in retinal pigment epithelial cells from rats with streptozotocin-induced diabetes mellitus. Western blot analysis, Reverse transcription-PCR, immunohistochemistry, and flow cytometry results showed increased expression of 3-nitrotyrosine, a peroxyntrite marker, as well as inducible nitric synthase and Fas/FasL, in retinal pigment epithelial cells. Puerarin reversed these changes, and results demonstrated that puerarin inhibited Fas/FasL expression and alleviated peroxyntrite injury to retinal pigment epithelial cells. These results suggested that puerarin inhibited production of inducible nitric oxide synthase and directly antagonized peroxyntrite injury in retinal pigment epithelial cells.

  2. [Research on the origins and development of the verse "eighteen antagonism" in Chinese material medica].

    Science.gov (United States)

    Yang, Huan; Fan, Xin-Sheng; Bian, Ya-Li; Li, Yun; Jiang, Chen-Xue

    2013-03-01

    The verse "eighteen antagonism" of Chinese materia medica is a kind of describing of drug nature concerning the incompatibility of drugs in compound prescription. Through organizing the medical books in different historical periods, it is found that the drugs in this verse basically coming from TAO Hong-jing's ben cao jing ji zhu (Variorum of Shennong's Classic of Materia Medica), while the style of verse mostly appeared during the Song-Jin-Yuan period was made. The formed verse was explained and supplemented further in the Ming Dynasty, the basis of which appeared in the Song-Jin-Yuan Dynasty, resulting in the increase of the number of antagonistic drugs and lengthy verse. The origin of the verse seen in Ru men shi qin (Confucians' Duties to Their Parents) and those in other books was not identical and was the most popular one after the Qing Dynasty, becoming the most popularly known even today. PMID:24135473

  3. Self-Regulation in Early Adolescence: Relations with Mother-Son Relationship Quality and Maternal Regulatory Support and Antagonism

    Science.gov (United States)

    Moilanen, Kristin L.; Shaw, Daniel S.; Fitzpatrick, Amber

    2010-01-01

    The purpose of the current investigation was to examine relations among maternal regulatory support, maternal antagonism, and mother-son relationship quality in relation to boys' self-regulation during early adolescence. As part of a larger longitudinal study on 263 low-income, ethnically diverse boys, multiple informants and methods were used to…

  4. The reduction of anti-cancer drug antagonism by the spatial protection of drugs with PLA-TPGS nanoparticles.

    Science.gov (United States)

    Tan, Guang-Rong; Feng, Si-Shen; Leong, David T

    2014-03-01

    Docetaxel (DCL) and tamoxifen (TAM) individually are potent drugs in the fight against breast cancer. However when used in combination, they become antagonistic because of differential metabolism of both drugs. We reasoned that by spatially protecting them from metabolizing enzymes with poly (lactide)-D-α-tocopheryl polyethylene glycol succinate (PLA-TPGS) nanoparticles (NPs), we might reduce this drug antagonism. We now report that the drug antagonism between DCL and TAM in MCF7 cell line, was significantly reduced when co-delivered in PLA-TPGS NPs. In addition, this effect of NPs attenuated at high drug concentrations. To investigate the role of NPs in the reduction of drug antagonism, we quantified cellular uptake of the fluorescent model drug coumarin 6 (C6) encapsulated in a rigorous permutation of drugs-nanoparticles ratios. NPs carrying C6 exhibited enhanced cellular uptake over their free C6 counterparts at correspondingly low drug concentrations. This led us to conclude that the reduction of drug antagonism by NPs is correlated to cellular uptake and being in NPs therefore protects both drugs until they are released intracellular for therapeutic anti-cancer effect. PMID:24439415

  5. SSX2 is a novel DNA-binding protein that antagonizes polycomb group body formation and gene repression

    DEFF Research Database (Denmark)

    Gjerstorff, Morten Frier; Relster, Mette Marie; Greve, Katrine Buch Viden;

    2014-01-01

    Polycomb group (PcG) complexes regulate cellular identity through epigenetic programming of chromatin. Here, we show that SSX2, a germline-specific protein ectopically expressed in melanoma and other types of human cancers, is a chromatin-associated protein that antagonizes BMI1 and EZH2 PcG body...

  6. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive.

    Directory of Open Access Journals (Sweden)

    Antoine eHuart

    2015-02-01

    Full Text Available Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease. Currently, inhibitors of the renin angiotensin system (RAS remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra with that of an angiotensin type 1 receptor antagonist (AT1a in the unilateral ureteral obstruction (UUO model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors.

  7. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive

    Science.gov (United States)

    Huart, Antoine; Klein, Julie; Gonzalez, Julien; Buffin-Meyer, Bénédicte; Neau, Eric; Delage, Christine; Calise, Denis; Ribes, David; Schanstra, Joost P.; Bascands, Jean-Loup

    2015-01-01

    Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin–angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors. PMID:25698969

  8. Metformin may antagonize Lin28 and/or Lin28B activity, thereby boosting let-7 levels and antagonizing cancer progression.

    Science.gov (United States)

    McCarty, Mark F

    2012-02-01

    Cancer cells with stem cell characteristics are harbored by most tumors, and are characterized by epithelial-mesenchymal transition (EMT) - which promotes invasive growth and metastasis - chemoresistance, and the capacity to reconstitute new tumors. Hence, the control or destruction of cancer stem cells should be a major goal of cancer management. The let-7 family of microRNAs has cancer suppressor activity, and recent evidence suggests that markedly reduced levels of let-7 are not only a typical feature of cancer stem cells, but may be largely responsible for cancer stemness. It is therefore particularly intriguing that metformin, a diabetes drug thought to have potential in the prevention and treatment of cancer, has recently been found to oppose cancer cell stemness, to markedly potentiate chemotherapeutic control of cancer in mouse xenograft models, and to notably boost let-7a levels in cancer stem cells. It is proposed that this latter effect of metformin may reflect AMPK-mediated inhibition of the expression or activity of Lin28/Lin28A, proteins which act post-transcriptionally to decrease the levels of all let-7 family members. The transcription of Lin28B is promoted by NF-kappaB and by Myc; hence, practical measures which antagonize NF-kappaB or Myc activity may complement the utility of metformin for boosting let-7 expression and controlling cancer stemness; salsalate, antioxidants, tyrosine kinase and cox-2 inhibitors, ribavirin, vitamin D, gamma-secretase inhibitors (when available), and parenteral curcumin may have some utility in this regard. Although the impact of histone deacetylase inhibitors on let-7 expression has not been assessed, there is reason to suspect that these drugs might complement let-7's impact on chemoresistance, EMT, and stemness. Multifocal strategies centering on metformin may have considerable potential for reversing cancer stemness and rendering advanced cancers more susceptible to long term control. PMID:22129484

  9. BEX1 Promotes Imatinib-Induced Apoptosis by Binding to and Antagonizing BCL-2

    OpenAIRE

    Qian Xiao; Yeting Hu; Yue Liu; Zhanhuai Wang; Haitao Geng; Lifeng Hu; Dengyong Xu; Ke Wang; Lei Zheng; Shu Zheng; Kefeng Ding

    2014-01-01

    An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function r...

  10. Frondoside A inhibits breast cancer metastasis and antagonizes prostaglandin E receptors EP4 and EP2.

    Science.gov (United States)

    Ma, Xinrong; Kundu, Namita; Collin, Peter D; Goloubeva, Olga; Fulton, Amy M

    2012-04-01

    Frondoside A, derived from the sea cucumber Cucumaria frondosa has demonstrable anticancer activity in several models, however, the ability of Frondoside A to affect tumor metastasis has not been reported. Using a syngeneic murine model of metastatic breast cancer, we now show that Frondoside A has potent antimetastatic activity. Frondoside A given i.p. to mice bearing mammary gland-implanted mammary tumors, inhibits spontaneous tumor metastasis to the lungs. The elevated Cyclooxygenase-2 activity in many malignancies promotes tumor growth and metastasis by producing high levels of PGE(2) which acts on the prostaglandin E receptors, chiefly EP4 and EP2. We examined the ability of Frondoside A to modulate the functions of these EP receptors. We now show that Frondoside A antagonizes the prostaglandin E receptors EP2 and EP4. (3)H-PGE(2) binding to recombinant EP2 or EP4-expressing cells was inhibited by Frondoside A at low μM concentrations. Likewise, EP4 or EP2-linked activation of intracellular cAMP as well as EP4-mediated ERK1/2 activation were also inhibited by Frondoside A. Consistent with the antimetastatic activity observed in vivo, migration of tumor cells in vitro in response to EP4 or EP2 agonists was also inhibited by Frondoside A. These studies identify a new function for an agent with known antitumor activity, and show that the antimetastatic activity may be due in part to a novel mechanism of action. These studies add to the growing body of evidence that Frondoside A may be a promising new agent with potential to treat cancer and may also represent a potential new modality to antagonize EP4. PMID:21761157

  11. Comparative analyses of reproductive structures in harvestmen (opiliones reveal multiple transitions from courtship to precopulatory antagonism.

    Directory of Open Access Journals (Sweden)

    Mercedes M Burns

    Full Text Available Explaining the rapid, species-specific diversification of reproductive structures and behaviors is a long-standing goal of evolutionary biology, with recent research tending to attribute reproductive phenotypes to the evolutionary mechanisms of female mate choice or intersexual conflict. Progress in understanding these and other possible mechanisms depends, in part, on reconstructing the direction, frequency and relative timing of phenotypic evolution of male and female structures in species-rich clades. Here we examine evolution of reproductive structures in the leiobunine harvestmen or "daddy long-legs" of eastern North America, a monophyletic group that includes species in which males court females using nuptial gifts and other species that are equipped for apparent precopulatory antagonism (i.e., males with long, hardened penes and females with sclerotized pregenital barriers. We used parsimony- and Bayesian likelihood-based analyses to reconstruct character evolution in categorical reproductive traits and found that losses of ancestral gift-bearing penile sacs are strongly associated with gains of female pregenital barriers. In most cases, both events occur on the same internal branch of the phylogeny. These coevolutionary changes occurred at least four times, resulting in clade-specific designs in the penis and pregenital barrier. The discovery of convergent origins and/or enhancements of apparent precopulatory antagonism among closely related species offers an unusual opportunity to investigate how major changes in reproductive morphology have occurred. We propose new hypotheses that attribute these enhancements to changes in ecology or life history that reduce the duration of breeding seasons, an association that is consistent with female choice, sexual conflict, and/or an alternative evolutionary mechanism.

  12. Comparative analyses of reproductive structures in harvestmen (opiliones) reveal multiple transitions from courtship to precopulatory antagonism.

    Science.gov (United States)

    Burns, Mercedes M; Hedin, Marshal; Shultz, Jeffrey W

    2013-01-01

    Explaining the rapid, species-specific diversification of reproductive structures and behaviors is a long-standing goal of evolutionary biology, with recent research tending to attribute reproductive phenotypes to the evolutionary mechanisms of female mate choice or intersexual conflict. Progress in understanding these and other possible mechanisms depends, in part, on reconstructing the direction, frequency and relative timing of phenotypic evolution of male and female structures in species-rich clades. Here we examine evolution of reproductive structures in the leiobunine harvestmen or "daddy long-legs" of eastern North America, a monophyletic group that includes species in which males court females using nuptial gifts and other species that are equipped for apparent precopulatory antagonism (i.e., males with long, hardened penes and females with sclerotized pregenital barriers). We used parsimony- and Bayesian likelihood-based analyses to reconstruct character evolution in categorical reproductive traits and found that losses of ancestral gift-bearing penile sacs are strongly associated with gains of female pregenital barriers. In most cases, both events occur on the same internal branch of the phylogeny. These coevolutionary changes occurred at least four times, resulting in clade-specific designs in the penis and pregenital barrier. The discovery of convergent origins and/or enhancements of apparent precopulatory antagonism among closely related species offers an unusual opportunity to investigate how major changes in reproductive morphology have occurred. We propose new hypotheses that attribute these enhancements to changes in ecology or life history that reduce the duration of breeding seasons, an association that is consistent with female choice, sexual conflict, and/or an alternative evolutionary mechanism. PMID:23762497

  13. RAB-7 antagonizes LET-23 EGFR signaling during vulva development in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Olga Skorobogata

    Full Text Available The Rab7 GTPase regulates late endosome trafficking of the Epidermal Growth Factor Receptor (EGFR to the lysosome for degradation. However, less is known about how Rab7 activity, functioning late in the endocytic pathway, affects EGFR signaling. Here we used Caenorhabditis elegans vulva cell fate induction, a paradigm for genetic analysis of EGFR/Receptor Tyrosine Kinase (RTK signaling, to assess the genetic requirements for rab-7. Using a rab-7 deletion mutant, we demonstrate that rab-7 antagonizes LET-23 EGFR signaling to a similar extent, but in a distinct manner, as previously described negative regulators such as sli-1 c-Cbl. Epistasis analysis places rab-7 upstream of or in parallel to lin-3 EGF and let-23 EGFR. However, expression of gfp::rab-7 in the Vulva Presursor Cells (VPCs is sufficient to rescue the rab-7(- VPC induction phenotypes indicating that RAB-7 functions in the signal receiving cell. We show that components of the Endosomal Sorting Complex Required for Transport (ESCRT-0, and -I, complexes, hgrs-1 Hrs, and vps-28, also antagonize signaling, suggesting that LET-23 EGFR likely transits through Multivesicular Bodies (MVBs en route to the lysosome. Consistent with RAB-7 regulating LET-23 EGFR trafficking, rab-7 mutants have increased number of LET-23::GFP-positive endosomes. Our data imply that Rab7, by mediating EGFR trafficking and degradation, plays an important role in downregulation of EGFR signaling. Failure to downregulate EGFR signaling contributes to oncogenesis, and thus Rab7 could possess tumor suppressor activity in humans.

  14. SB-224289 Antagonizes the Antifungal Mechanism of the Marine Depsipeptide Papuamide A.

    Directory of Open Access Journals (Sweden)

    Chelsi D Cassilly

    Full Text Available In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS synthase (Cho1p was developed based on antagonism of the toxin papuamide A (Pap-A. Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type Candida albicans, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the CHO1 gene (cho1ΔΔ do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A, but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins.

  15. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Tarulli, Gerard; Zarnke, Allison L; Bourgo, Ryan J; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G; Raj, Ganesh V; Hickey, Theresa E; Tilley, Wayne D; Greene, Geoffrey L

    2016-06-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored. PMID:27386569

  16. Taurine antagonized oxidative stress injury induced by homocysteine in rat vascular smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    Lin CHANG; Jian-xin XU; Jing ZHAO; Yong-zheng PANG; Chao-shu TANG; Yong-fen QI

    2004-01-01

    AIM: To observe protective effects of taurine on reactive oxygen species generation induced by homocysteine in rat vascular smooth muscle cells (VSMC). METHODS: Rat VSMC was incubated with various concentrations of homocysteine and taurine. The lactate dehydrogenase (LDH) activity which released into culture medium was elevated as an indicator for VSMC injury. The reactive oxygen species (ROS) - hydrogen peroxide (H2O2) and superoxide anion (O2- )were measured with luminol or lucigenin chemiluminescences method, and the mitochondria Mn-superoxide dismutase (Mn-SOD) and catalase (CAT) were also measured in treated VSMC. RESULTS: LDH leakage from cultured VSMC treated with homocystenie, was increased (P<0.01 vs control), and it was markedly inhibited when co-incubated with taurine (P<0.01). Homocysteine induced H2O2 generation from VSMC in a concentration dependent manner (P<0.01 vs control). However, taurine (5, 10, and 20 mmol/L) significantly antagonized 0.5 mmol/L homocysteine-induced H2O2 generation in VSMC in a concentration dependent manner (P<0.01 vs homocysteine alone group), although taurine itself did not alter the H2O2 generation in VSMC (P>0.05 vs control).In this study, the superoxide anion in VSMC was not detectable by chemiluminent method. In addition, treatment of VSMC with taurine increased mitochondria Mn-SOD and CAT activity in a concentration dependent manner (P<0.05), but homocysteine decreased mitochondria Mn-SOD and CAT activity (P<0.01 vs control). In addition,co-administration of taurine markedly ameliorated homocysteine-induced inhibition of Mn-SOD and CAT activity in VSMC (P<0.01 vs homocysteine alone group). CONCLUSION: Taurine antagonized the effects of homocysteine on ROS generation and anti-oxidant enzyme activities in rat VSMC in vitro.

  17. Des-Gamma-Carboxy Prothrombin (DCP Antagonizes the Effects of Gefitinib on Human Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Yu-Sheng Zhang

    2015-01-01

    Full Text Available Background/Aims: Des-gamma-carboxy prothrombin (DCP, an aberrant prothrombin produced by hepatocellular carcinoma (HCC cells, is known as a marker for HCC. Recent studies indicated that high levels of DCP are associated with the malignant potential of HCC. In this study, we aimed to investigate the association of DCP with gefitinib treatment failure in HCC and whether DCP counteracts gefitinib-induced growth inhibition and apoptosis of HCC. Methods: The experiments were performed in HCC cell lines HepG2 and PLC/PRF/5. The effects of gefitinib on HCC in the presence or absence of DCP were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT assay. Apoptotic cells were identified by Annexin V-FITC/PI staining. Western blotting was performed to analyze the expressions of molecules related to the apoptotic caspase-dependent pathway and epidermal growth factor receptor (EGFR pathway. Results: Gefitinib inhibited HCC cell proliferation and induced apoptosis in HCC cells. The effects of gefitinib on HCC cells were antagonized by DCP. In the presence of DCP, HCC cells were resistant to the gefitinib-induced inhibition of proliferation and stimulation of apoptosis. DCP prevented the activation of the apoptotic caspase-dependent pathway induced by gefitinib. These antagonistic effects of DCP also arose from its ability to up-regulate EGFR, c-Met and hepatocyte growth factor (HGF in HCC cells. Conclusion: DCP antagonized gefitinib-induced HCC cell growth inhibition by counteracting apoptosis and up-regulating the EGFR pathway. High levels of DCP might thus lead to low response rates or possibly no response to gefitinib in patients with HCC.

  18. The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Dowejko, Albert, E-mail: Albert.Dowejko@klinik.uni-regensburg.de [Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg (Germany); Bauer, Richard; Bauer, Karin [Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg (Germany); Mueller-Richter, Urs D.A. [Department of Oral and Maxillofacial Plastic Surgery, University of Wuerzburg, Pleicherwall 2, 97070 Wuerzburg (Germany); Reichert, Torsten E. [Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg (Germany)

    2012-03-10

    There is a growing evidence that the human homologue of the Drosophila headcase (HECA) plays an important role in human carcinogenesis. So far specific protein interaction partners and affected signaling pathways of HECA are still elusive. In a recent study we showed that HECA overexpression in oral squamous-cell carcinoma (OSCC) keratinocytes has tumor suppressive effects resulting in a recuperation of cell cycle control concerning the entry and progression of S-phase, G2- and M-phase. Currently, quantitative RT-PCR and immunohistochemical analysis of primary tumor tissue from OSCC patients demonstrate that HECA expression is markedly decreased compared to normal control patients with abundant HECA expression. Additionally, there is nearly no HECA expression in OSCC metastases. Here, we show that HECA expression is negatively controlled by the Wnt-pathway and TCF4, a Wnt related transcription factor, binds to the HECA promoter. Furthermore, immunocytochemistry reveals colocalization of HECA with the cyclin dependent kinase CDK9. Immunoprecipitation experiments and proximity ligation assays further reveal an interaction of HECA with CDK2, CDK9, Cyclin A and Cyclin K, a direct transcriptional target of the p53 tumor suppressor. Silencing HECA in OSCC cell lines leads to a significant increase of cell division and a markedly increased resistance against the chemotherapeutic cisplatin. On the contrary, HECA overexpressing OSCC cell lines show decreased resistance of OSCC cells against cisplatin. Therefore, HECA could be considered as future therapeutic agent against Wnt-dependent tumor progression. -- Highlights: Black-Right-Pointing-Pointer HECA is a new cell cycle regulator with anti-tumor features in head and neck cancer. Black-Right-Pointing-Pointer During tumor progression HECA mRNA and protein expression decrease. Black-Right-Pointing-Pointer The HECA promotor is a direct target of the Wnt/beta-catenin/TCF-pathway. Black-Right-Pointing-Pointer The HECA protein

  19. Disrupting the flow : How brief silences in group conversations affect social needs

    NARCIS (Netherlands)

    Koudenburg, Namkje; Postmes, Tom; Gordijn, Ernestine H.

    2011-01-01

    We all know the awkward feeling when a conversation is disrupted by a brief silence. This paper studies why such moments can be unsettling. We suggest that silences are particularly disturbing if they disrupt the conversational flow. In two experiments we examined the effects of a single brief insta

  20. The Relationship between Organizational Silence and Burnout among Academicians: A Research on Universities in Turkey

    Science.gov (United States)

    Akin, Ugur; Ulusoy, Tarik

    2016-01-01

    The aim of this research is to analyze the relationship between organizational silence and burnout levels of academicians. The study group consisted of 190 academicians, who work in 17 state universities that are located in 15 different provinces of Turkey. Data were collected through Causes of Faculty Members' Silence Scale and Maslach Burnout…

  1. Self-Silencing, Emotional Awareness, and Eating Behaviors in College Women

    Science.gov (United States)

    Shouse, Sarah H.; Nilsson, Johanna

    2011-01-01

    Self-silencing (or the suppression of expressing one's thoughts, feelings, and needs) can have a negative impact on the mental health of women, from depression to disordered eating behaviors. The authors examined the relationship between self-silencing and disordered eating as well as intuitive eating. The authors also explored whether emotional…

  2. Performing Silence: Gender, Violence, and Resistance in Women's Narratives from Lahaul, India

    Science.gov (United States)

    Bhattacharya, Himika

    2009-01-01

    This article presents two different ways of understanding silence, through a discussion of women's narratives of violence from Lahaul, India. Here I illustrate how feminist ethnography works its way into re-conceptualizing silence as a tool women use to resist existing patriarchal discourses of honor, tribe and nation. (Contains 1 note.)

  3. Silence as Right, Choice, Resistance and Strategy among Chinese "Me Generation" Students: Implications for Pedagogy

    Science.gov (United States)

    Ha, Phan Le; Li, Binghui

    2014-01-01

    The topic of silence and "the Chinese learner" has been extensively studied often in relation to cross-cultural adjustment, intercultural issues, learning styles, language ability and differences of classroom expectations. These studies have often led to recommendations to understand silence and "the Chinese learner" in more…

  4. Horreur et silence : le personnage de Pierre Cange dans l’œuvre narrative de Vercors

    Directory of Open Access Journals (Sweden)

    Elisabetta Sibilio

    2015-11-01

    Full Text Available Vercors, who achieved fame thanks to his first novel, Le silence de la mer, published undercover in 1942, makes silence one of the main themes in his work. Silence, which is the paradoxical expression of what Vercors calls “la qualité d’homme”, appears in his work according to two major categories: on the one hand the proud and resilient silence of the protagonist of Silence de la mer or of Arnaud, the main character of the short story Le démenti, who loses his life for having maintained an obstinate silence in the hands of his torturers; on the other hand, the guilty and desperate shameful silence of those who had lost their own humanity when faced with the horror of the camps or had hoped to save their lives by col-laborating with the enemy. This paper will examine three of Vercors’ texts, Les armes de la nuit (1946, La puissance du jour (1951 and Le tigre d’Anvers (1986, which have Pierre Cange as protagonist, a member of the Resistance, deported, who through his own experience is faced with the funda-mental theme of silence.

  5. Suppressor of RNA silencing encoded by Rice gall dwarf virus genome segment 11

    Institute of Scientific and Technical Information of China (English)

    LIU FuXiu; ZHAO Qin; RUAN XiaoLei; HE YunWei; LI HuaPing

    2008-01-01

    Rice gall dwarf virus (RGDV) is an important rice pathogen in China and Southeast Asia. However, little is known about the molecular mechanisms of RGDV interactions with plant cells. Here, we have identi-fied an RGDV protein, Pns11, which acts as a suppressor of RNA silencing in coinfiltration assays with the reporter, green fluorescent protein (GFP) in transgenic Nicotiana bentharniana line 16c carrying GFP. Pns11 suppressed local and systemic silencing induced by sense RNA. The spread of mobile FINA si-lencing signals was blocked or inactivated by Pns11. Expression of Pns11 also enhanced Potato virus X pathogenicity in N. benthamiana. This suppressor could reduce, but not eliminate, siRNA in the local and systemic RNA silencing suppression assays, suggesting that Pns11 functions by interfering with initial stages of RNA silencing.

  6. The dangerous role of silence in the relationship between trauma and violence: a group response.

    Science.gov (United States)

    Phillips, Suzanne B

    2015-01-01

    This article considers that somewhere in the space between violence and trauma is dangerous silence. Silence intensifies the impact of trauma, and trauma that goes unspoken, un-witnessed, and unclaimed too often "outs itself" as more violence to self or others. Relevant empirical evidence on the impact of civilian interpersonal violence, combat trauma, school shootings, bullying, and domestic violence confirms this tragic cycle. Crucial to addressing the danger of silence in this cycle, the article examines the centrality of silence existentially, neuropsychologically, psychologically, developmentally, interpersonally, and culturally in relation to violence. The bridge to voicing and assimilating the unspeakable is empathic connection with others. Drawing upon two different types of group programs, the article demonstrates that group can serve as that bridge. Group process has the potential to undo the dangerous role of silence in the relationship of trauma and violence.

  7. Stability of Barley stripe mosaic virus-induced gene silencing in barley

    DEFF Research Database (Denmark)

    Bruun-Rasmussen, Marianne; Madsen, Christian Toft; Jessing, Stine;

    2007-01-01

    for barley and wheat; however, silencing using this vector is generally transient, with efficient silencing often being confined to the first two or three systemically infected leaves. To investigate this further, part of the barley Phytoene desaturase (PDS) gene was inserted into BSMV and the...... length influenced stability but not efficiency of VIGS. Silencing was transient in most cases; however, the decrease in PDS mRNA levels measured by qRT-PCR began earlier and lasted longer than the photobleaching. Occasionally, silencing persisted and could be transmitted through seed as well as via......Virus-induced gene silencing (VIGS) can be used as a powerful tool for functional genomics studies in plants. With this approach, it is possible to target most genes and downregulate the messenger (m)RNA in a sequence-specific manner. Barley stripe mosaic virus (BSMV) is an established VIGS vector...

  8. Inheritable Silencing of Endogenous Genes by Hit-and-Run Targeted Epigenetic Editing.

    Science.gov (United States)

    Amabile, Angelo; Migliara, Alessandro; Capasso, Paola; Biffi, Mauro; Cittaro, Davide; Naldini, Luigi; Lombardo, Angelo

    2016-09-22

    Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. Here, we repurpose the endogenous retroviruses' silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. This was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo DNA methylation, thus ensuring long-term memory of the repressive epigenetic state. Silencing was highly specific, as shown by genome-wide analyses, sharply confined to the targeted locus without spreading to nearby genes, resistant to activation induced by cytokine stimulation, and relieved only by targeted DNA demethylation. We demonstrate the portability of this technology by multiplex gene silencing, adopting different DNA binding platforms and interrogating thousands of genomic loci in different cell types, including primary T lymphocytes. Targeted epigenome editing might have broad application in research and medicine. PMID:27662090

  9. Hearing the Silence: Children’s Voices on Violence

    Directory of Open Access Journals (Sweden)

    Kathryn S. Collins

    2003-05-01

    Full Text Available Each year more than five million children in the United States are exposed to traumatizing events in their communities. This paper presents a discussion of multiple areas in violence and victimization research that needs to be continued as well as provides suggestions on how to un-silence child survivors through bridging the gaps between research and practice. It reviews the overarching problem of violence in the U.S. at the domestic and global levels and the effects of victimization. Suggestions on how to study possible mediators and moderators of victimization and individual and family adjustment, including: 1 The ecological perspective; 2 Court process and verdict; and 3Utilization of victim services, are explored. Finally, a rationale and examples of combining qualitative and quantitative methods in future research that uses children’s attributions of violence as a mediator are presented.

  10. Revival of Silenced Echo and Quantum Memory for Light

    CERN Document Server

    Damon, V; Louchet-Chauvet, A; Chanelière, T; Gouët, J -L Le

    2011-01-01

    We propose an original quantum memory protocol. It belongs to the class of rephasing processes and is closely related to two-pulse photon echo. It is known that the strong population inversion produced by the rephasing pulse prevents the plain two-pulse photon echo from serving as a quantum memory scheme. Indeed gain and spontaneous emission generate prohibitive noise. A second $\\pi$-pulse can be used to simultaneously reverse the atomic phase and bring the atoms back into the ground state. Then a secondary echo is radiated from a non-inverted medium, avoiding contamination by gain and spontaneous emission noise. However, one must kill the primary echo, in order to preserve all the information for the secondary signal. In the present work, spatial phase mismatching is used to silence the standard two-pulse echo. An experimental demonstration is presented.

  11. Linking DNA replication to heterochromatin silencing and epigenetic inheritance

    Institute of Scientific and Technical Information of China (English)

    Qing Li; Zhiguo Zhang

    2012-01-01

    Chromatin is organized into distinct functional domains.During mitotic cell division,both genetic information encoded in DNA sequence and epigenetic information embedded in chromatin structure must be faithfully duplicated.The inheritance of epigenetic states is critical in maintaining the genome integrity and gene expression state.In this review,we will discuss recent progress on how proteins known to be involved in DNA replication and DNA replication-coupled nucleosome assembly impact on the inheritance and maintenance of heterochromatin,a tightly compact chromatin structure that silences gene transcription.As heterochromatin is important in regulating gene expression and maintaining genome stability,understanding how heterochromatin states are inherited during S phase of the cell cycle is of fundamental importance.

  12. Providing Eligibility Criteria On Turbocharger Filter Silencer Design Processes

    Directory of Open Access Journals (Sweden)

    Adem GÜLERYÜZ

    2013-06-01

    Full Text Available Supply of ventilation air to either the engine room or diesel engine directly affects engine performances. Main criteria is supply of air volume and pressure into the cylinder. When Air starts to come until the cylinders, there many points which behave as restrictions. These are ventilation grills. ventilation fans, ventilation casings, misteliminators, manual or pneumatically adjusted fan dampers, number of bending of ventilation casing, cleanness of casings, air flow speed, air filters, turbocharger filter and silencers, engine’s scavenge air cooler restrictions. Here, we focused on optimum required air need through turbocharger for local diesel engine. While researching actual need, new turbocharger filter were designed and manufactured for engine manufacturer.

  13. SOCS3 silencing attenuates eosinophil functions in asthma patients.

    Science.gov (United States)

    Zafra, Ma Paz; Cañas, Jose A; Mazzeo, Carla; Gámez, Cristina; Sanz, Veronica; Fernández-Nieto, Mar; Quirce, Santiago; Barranco, Pilar; Ruiz-Hornillos, Javier; Sastre, Joaquín; del Pozo, Victoria

    2015-01-01

    Eosinophils are one of the key inflammatory cells in asthma. Eosinophils can exert a wide variety of actions through expression and secretion of multiple molecules. Previously, we have demonstrated that eosinophils purified from peripheral blood from asthma patients express high levels of suppressor of cytokine signaling 3 (SOCS3). In this article, SOCS3 gene silencing in eosinophils from asthmatics has been carried out to achieve a better understanding of the suppressor function in eosinophils. SOCS3 siRNA treatment drastically reduced SOCS3 expression in eosinophils, leading to an inhibition of the regulatory transcription factors GATA-3 and FoxP3, also interleukin (IL)-10; in turn, an increased STAT3 phosphorilation was observed. Moreover, SOCS3 abrogation in eosinophils produced impaired migration, adhesion and degranulation. Therefore, SOCS3 might be regarded as an important regulator implicated in eosinophil mobilization from the bone marrow to the lungs during the asthmatic process. PMID:25764157

  14. SOCS3 Silencing Attenuates Eosinophil Functions in Asthma Patients

    Directory of Open Access Journals (Sweden)

    Mª Paz Zafra

    2015-03-01

    Full Text Available Eosinophils are one of the key inflammatory cells in asthma. Eosinophils can exert a wide variety of actions through expression and secretion of multiple molecules. Previously, we have demonstrated that eosinophils purified from peripheral blood from asthma patients express high levels of suppressor of cytokine signaling 3 (SOCS3. In this article, SOCS3 gene silencing in eosinophils from asthmatics has been carried out to achieve a better understanding of the suppressor function in eosinophils. SOCS3 siRNA treatment drastically reduced SOCS3 expression in eosinophils, leading to an inhibition of the regulatory transcription factors GATA-3 and FoxP3, also interleukin (IL-10; in turn, an increased STAT3 phosphorilation was observed. Moreover, SOCS3 abrogation in eosinophils produced impaired migration, adhesion and degranulation. Therefore, SOCS3 might be regarded as an important regulator implicated in eosinophil mobilization from the bone marrow to the lungs during the asthmatic process.

  15. Silencing of voices in a Swedish science classroom

    Science.gov (United States)

    Ramos de Robles, S. Lizette

    2016-09-01

    From a sociocultural perspective, I discuss data from a Swedish science classroom presented in María Gómez's article "Student Explanations of their Science Teachers' Assessments, Grading Practices, and How they learn Science". In this discussion, I focus on the need to change existing conceptions of assessment in the teaching and learning of science. Next, I talk about the importance of taking into consideration the dialectic between agency and passivity as filters in order to understand what student silence may signify in science classes as well as in relation to their perceptions of assessment. I conclude with the importance of the teacher's role in developing formative assessment, along with the challenges in developing assessments which transform science education into a relevant field of knowledge for both students and society at large.

  16. LNA-antisense rivals siRNA for gene silencing

    DEFF Research Database (Denmark)

    Jepsen, Jan Stenvang; Wengel, Jesper; Stenvang, Jan

    2004-01-01

    Locked nucleic acid (LNA) is a class of nucleic acid analogs possessing unprecedented binding affinity toward complementary DNA and RNA while obeying the Watson-Crick base-pairing rules. For efficient gene silencing in vitro and in vivo, fully modified or chimeric LNA oligonucleotides have been...... applied. LNA oligonucleotides are commercially available, can be transfected using standard techniques, are non-toxic, lead to increased target accessibility, can be designed to activate RNase H, and function in steric block approaches. LNA-Antisense, including gapmer LNA containing a central DNA...... or phosphorothioate-DNA segment flanked by LNA gaps, rivals siRNA as the technology of choice for target validation and therapeutic applications....

  17. Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

    Science.gov (United States)

    Basting, Tyler M; Burke, Peter G R; Kanbar, Roy; Viar, Kenneth E; Stornetta, Daniel S; Stornetta, Ruth L; Guyenet, Patrice G

    2015-01-14

    In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN.

  18. Ways to Promote the Classroom Participation of International Students by Understanding the Silence of Japanese University Students

    Science.gov (United States)

    Kim, Soonhyang; Ates, Burcu; Grigsby, Yurimi; Kraker, Stefani; Micek, Timothy A.

    2016-01-01

    The authors explored the role of silence and deciphered its meaning and usefulness as a teaching and learning strategy for Japanese students through a survey of Japanese university students in their home country. This study has revealed that participant responses were evenly divided among comfortable with silence, uncomfortable with silence, and…

  19. Registration Antagonism in the Property Law%物权法上的登记对抗主义

    Institute of Scientific and Technical Information of China (English)

    姚虹

    2014-01-01

    Due to the adoption of duality structure of property rights changes,it comes to focus on how to ex-plain the existence of registration antagonism in theory and practice. Announcement proof doctrine and regis-tration antagonism have their legislation background with little difference. The emerging registration antagonism represents the product of specific product trade and prevailing liberalism. So-called " antagonism" ,essential-ly,means the strength of right effect,and its difference to priority lies in its strong exclusion. In order to en-sure the logic of property law system,we advocate the legislation mode of registration antagonism explained by trust protection theory,and attempt to discuss the definition of the third person scope of registration antagonism in the view of matter-media legal relationship.%由于物权法上物权变动二元化结构模式的采纳,相应地,如何解释作为例外存在的登记对抗主义成为理论与实践关注的焦点。公示要件主义与登记对抗主义模式有着不完全相同的立法背景,登记对抗主义的问世是特定物交易与自由主义盛行的产物。所谓“对抗”实质上就是指权利效力的强弱,与优先权不同之处在于其权利之间强烈的排斥性。为保持物权体系逻辑性,我们主张依信赖保护说解释登记对抗立法模式,并尝试从以物为媒介建立的法律关系视角来探讨登记对抗主义第三人范围的界定。

  20. Apparent ploidy effects on silencing are post-transcriptional at HML and telomeres in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Jenny M McLaughlan

    Full Text Available The repression of genes in regions of heterochromatin is known as transcriptional silencing. It occurs in a wide range of organisms and can have importance in adaptation to the environment, developmental changes and disease. The model organism Saccharomyces cerevisiae has been used for many years to study transcriptional silencing, but until recently no study has been made in relation to ploidy. The aim of this work was to compare transcriptional silencing in haploids and diploids at both telomeres and the hidden mating-type (HM loci. Transcriptional silencing was assayed, by growth on 5-fluoroorotic acid (5-FOA media or by flow cytometry, on strains where a telomere or HM locus was marked. RNA levels were measured by quantitative RT-PCR to confirm that effects were transcriptional. 5-FOA assays and flow cytometry were consistent with transcriptional silencing at telomeres and at HML being reduced as ploidy increases which agreed with conclusions in previous publications. However, QRT-PCR revealed that transcriptional silencing was unaffected by ploidy and thus protein levels were increasing independently of RNA levels. At telomere XI left (XI-L, changes in protein level were strongly influenced by mating-type, whereas at HML mating-type had much less influence. The post-transcriptional effects seen in this study, illustrate the often ignored need to measure RNA levels when assaying transcriptional silencing in Saccharomyces cerevisiae.

  1. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells

    Science.gov (United States)

    Garcia-Perez, Jose L.; Morell, Maria; Scheys, Joshua O.; Kulpa, Deanna A.; Morell, Santiago; Carter, Christoph C.; Hammer, Gary D.; Collins, Kathleen L.; O’Shea, K. Sue; Menendez, Pablo; Moran, John V.

    2010-01-01

    Long INterspersed Element-1 (LINE-1 or L1) retrotransposition continues to impact human genome evolution1,2. L1s can retrotranspose in the germline, during early development, and in select somatic cells3,4,5,6,7,8; however, the host response to L1 retrotransposition remains largely unexplored. Here, we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors (IHDACs) rapidly reverses this silencing, and chromatin immunoprecipitation (ChIP) experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing also was observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukemia virus (MMLV) or human immunodeficiency virus (HIV), suggesting these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, per se, is not sufficient to reactivate previously silenced reporter genes. Thus, our data suggest that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition. PMID:20686575

  2. Epigenetic transcriptional silencing and 5-azacytidine-mediated reactivation of a complex transgene in rice.

    Science.gov (United States)

    Kumpatla, S P; Teng, W; Buchholz, W G; Hall, T C

    1997-01-01

    Despite a growing number of reports indicating non-Mendelian inheritance of transgene expression in monocots, no detailed description of the structure and stability of the transgene exists for transformants generated by direct DNA-transfer techniques, making the cause for these observations difficult to determine. In this paper we describe the complex organization of Btt cryIIIA and bar transgenes in rice (Oryza sativa L.) that displayed aberrant segregation in R1 progeny. Silencing rather than rearrangement of the bar gene was implicated because the herbicide-sensitive R1 plants had a DNA hybridization profile identical to that of the resistant R0 parent and R1 siblings. Genomic DNA analysis revealed substantial methylation of the Ubi1/bar sequences in silenced plants and, to a lesser degree, in herbicide-resistant plants, suggesting that the transgene locus was potentiated for silencing. Nuclease protection and nuclear run-on assays confirmed that silencing was due to transcriptional inactivation. Treatment of R2 progeny of silenced plants with 5-azacytidine resulted in demethylation of the Ubi1 promoter and reactivation of bar gene expression, demonstrating a functional relationship for methylation in gene silencing. These findings indicate that methylation-based silencing may be frequent in cereals transformed by direct DNA protocols that insert multiple, often rearranged sequences. PMID:9342860

  3. The physics of chromatin silencing: Bi-stability and front propagation

    Science.gov (United States)

    Sedighi, Mohammad

    A mean-field dynamical model of chromatin silencing in budding yeast is provided and the conditions giving rise to two states: one silenced and another un-silenced, is studied. Based on these conditions, the space of control parameters is divided into two distinct regions of mono-stable and bi-stable solutions (the bifurcation diagram). Then, considering both the discrete and continuous versions of the model, the formation of a stable boundary between the silenced and un-silenced areas on DNA is investigated. As a result, a richer phase diagram is provided. The dynamics of the boundary is also studied under different conditions. Consequently, assuming negative feedback due to possible depletion of silencing proteins, the model explains a paradoxical epigenetic behavior of yeast that happens under some mutation. A stochastic treatment of the model is also considered to verify the results of the mean-field approximation and also to understand the role of intrinsic noise at single cell level. This model could be used as a general guide to discuss chromatin silencing in many organisms.

  4. RNA-Interference Components Are Dispensable for Transcriptional Silencing of the Drosophila Bithorax-Complex

    KAUST Repository

    Cernilogar, Filippo M.

    2013-06-13

    Background:Beyond their role in post-transcriptional gene silencing, Dicer and Argonaute, two components of the RNA interference (RNAi) machinery, were shown to be involved in epigenetic regulation of centromeric heterochromatin and transcriptional gene silencing. In particular, RNAi mechanisms appear to play a role in repeat induced silencing and some aspects of Polycomb-mediated gene silencing. However, the functional interplay of RNAi mechanisms and Polycomb group (PcG) pathways at endogenous loci remains to be elucidated.Principal Findings:Here we show that the endogenous Dicer-2/Argonaute-2 RNAi pathway is dispensable for the PcG mediated silencing of the homeotic Bithorax Complex (BX-C). Although Dicer-2 depletion triggers mild transcriptional activation at Polycomb Response Elements (PREs), this does not induce transcriptional changes at PcG-repressed genes. Moreover, Dicer-2 is not needed to maintain global levels of methylation of lysine 27 of histone H3 and does not affect PRE-mediated higher order chromatin structures within the BX-C. Finally bioinformatic analysis, comparing published data sets of PcG targets with Argonaute-2-bound small RNAs reveals no enrichment of these small RNAs at promoter regions associated with PcG proteins.Conclusions:We conclude that the Dicer-2/Argonaute-2 RNAi pathway, despite its role in pairing sensitive gene silencing of transgenes, does not have a role in PcG dependent silencing of major homeotic gene cluster loci in Drosophila. © 2013 Cernilogar et al.

  5. A vector library for silencing central carbon metabolism genes with antisense RNAs in Escherichia coli.

    Science.gov (United States)

    Nakashima, Nobutaka; Ohno, Satoshi; Yoshikawa, Katsunori; Shimizu, Hiroshi; Tamura, Tomohiro

    2014-01-01

    We describe here the construction of a series of 71 vectors to silence central carbon metabolism genes in Escherichia coli. The vectors inducibly express antisense RNAs called paired-terminus antisense RNAs, which have a higher silencing efficacy than ordinary antisense RNAs. By measuring mRNA amounts, measuring activities of target proteins, or observing specific phenotypes, it was confirmed that all the vectors were able to silence the expression of target genes efficiently. Using this vector set, each of the central carbon metabolism genes was silenced individually, and the accumulation of metabolites was investigated. We were able to obtain accurate information on ways to increase the production of pyruvate, an industrially valuable compound, from the silencing results. Furthermore, the experimental results of pyruvate accumulation were compared to in silico predictions, and both sets of results were consistent. Compared to the gene disruption approach, the silencing approach has an advantage in that any E. coli strain can be used and multiple gene silencing is easily possible in any combination.

  6. Randomly Amplified Polymorphic DNA of Trichoderma isolates and antagonism against Rhizoctonia solani

    Directory of Open Access Journals (Sweden)

    Larissa Brandão Góes

    2002-06-01

    Full Text Available Random Amplified Polymorphic DNA (RAPD procedure was used to examine the genetic variability among fourteen isolates of Trichoderma and their ability to antagonize Rhizoctonia solani using a dual-culture assay for correlation among RAPD products and their hardness to R. solani. Seven oligodeoxynucleotide primers were selected for the RAPD assays which resulted in 197 bands for 14 isolates of Trichoderma. The data were entered into a binary matrix and a similarity matrix was constructed using DICE similarity (SD index. A UPGMA cluster based on SD values was generated using NTSYS (Numerical Taxonomy System, Applied Biostatistics computer program. A mean coefficient of similarity obtained for pairwise comparisons among the most antagonics isolates was around 40%. The results presented here showed that the variability among the isolates of Trichoderma was very high. No relationship was found between the polymorphism showed by the isolates and their hardness, origin and substrata.A técnica de RAPD (Random Amplified Polymorphic DNA foi utilizada para examinar a variabilidade genética em quatorze isolados de Trichoderma além de sua capacidade de antagonizar o fungo fitopatogênico Rhizoctonia solani usando pareamento in vitro, e a possível relação entre perfís de RAPD e agressividade dos isolados de Trichoderma a R. solani. Foram selecionados sete primers para os ensaios de RAPD, os quais produziram 197 bandas. Os dados foram introduzidos no programa de computador NTSYS (Numerical Taxonomy System, Applied Biostatisticsna forma de uma matrix binária, sendo construída uma matriz de similaridade utilizando-se o coeficiente de similaridade de DICE (SD e baseado nos valores SD, pelo método de agrupamento UPGMA um dendrograma. Observou-se que o grau de similaridade das amostras que apresentaram melhor desempenho antagônico foi bastante baixo, em torno de 40%. Os resultados demonstraram que a variabilidade entre os isolados de Trichoderma é muito

  7. MGA2 and SPT23 are modifiers of transcriptional silencing in yeast.

    OpenAIRE

    Dula, M L; Holmes, S G

    2000-01-01

    Transcriptional silencing at the HM loci and telomeres in yeast depends on several trans-acting factors, including Rap1p and the Sir proteins. The SUM1-1 mutation was identified by its ability to restore silencing to strains deficient in one or more of these trans-acting factors. The mechanism by which SUM1-1 bypasses the requirement for silencing proteins is not known. We identified four loci that when reduced in dosage in diploid strains increase the ability of SUM1-1 strains to suppress si...

  8. RNAi-induced silencing of embryonic tryptophan oxygenase in the Pyralid moth, Plodia interpunctella.

    Science.gov (United States)

    Fabrick, Jeffrey A; Kanost, Michael R; Baker, James E

    2004-01-01

    Gene silencing through the introduction of double-stranded RNA (RNA interference, RNAi) provides a powerful tool for the elucidation of gene function in many systems, including those where genomics and proteomics are incomplete. The use of RNAi technology for gene silencing in Lepidoptera has lacked significant attention compared to other systems. To demonstrate that RNAi can be utilized in the lepidopteran, Plodia interpunctella, we cloned a cDNA for tryptophan oxygenase, and showed that silencing of tryptophan oxygenase through RNAi during embryonic development resulted in loss of eye-color pigmentation. The complete amino acid sequence of Plodia tryptophan oxygenase can be accessed through NCBI Protein Database.

  9. The C. elegans CSR-1 Argonaute pathway counteracts epigenetic silencing to promote germline gene expression

    OpenAIRE

    Seth, Meetu; Shirayama, Masaki; Gu, Weifeng; Ishidate, Takao; Conte, Darryl; Mello, Craig C

    2013-01-01

    Organisms can develop adaptive sequence-specific immunity by re-expressing pathogen-specific small RNAs that guide gene silencing. For example, the C. elegans PIWI-Argonaute/piRNA pathway recruits RNA-dependent RNA polymerase RdRP to foreign sequences to amplify a trans-generational small RNA-induced epigenetic silencing signal (termed RNAe). Here we provide evidence that in addition to an adaptive memory of silenced sequences, C. elegans can also develop an opposing adaptive memory of expres...

  10. Honoring silence and valuing community: living leadership in 21st century teaching-learning.

    Science.gov (United States)

    Backer Condon, Barbara; Hegge, Margaret

    2014-04-01

    Leadership is a very personal concept. The methods implemented by leaders often reflect philosophical beliefs and theoretical underpinnings. This column, while recognizing that leadership styles are indeed personal, proffers living leadership in nursing education through two key leadership attitudes. These attitudes are honoring silence and valuing community. Honoring silence is discussed as recognizing the multiple dimensions of silence, and valuing community is presented in light of the humanbecoming community models change concepts: moving-initiating, anchoring-shifting, and pondering-shaping. PMID:24740944

  11. Review of the development of safety and relief valve silencers for steam discharge

    Energy Technology Data Exchange (ETDEWEB)

    Crawford, C.J.

    1988-01-01

    The progress made by the Central Electricity Generating Board (CEGB) in the development of silencers for the control of boiler safety valve and relief valve noise is reviewed. System noise sources and the formulation of environmental noise criteria are discussed; the silencer design philosophy adopted by the CEGB is described and the progressive improvements are charted to demonstrate the advances made over earlier practices. The results of this work are design concepts which provide silencers which are suitable for application to any of the CEGB's steam valve vent systems and are capable of meeting stringent neighbourhood noise criteria.

  12. The 2b protein of Asparagus virus 2 functions as an RNA silencing suppressor against systemic silencing to prove functional synteny with related cucumoviruses.

    Science.gov (United States)

    Shimura, Hanako; Masuta, Chikara; Yoshida, Naoto; Sueda, Kae; Suzuki, Masahiko

    2013-08-01

    Asparagus virus 2 (AV-2) is a member of the genus Ilarvirus in the family Bromoviridae. We cloned the coat protein (CP) and the 2b protein (2b) genes of AV-2 isolates from asparagus plants from various regions and found that the sequence for CP and for 2b was highly conserved among the isolates, suggesting that AV-2 from around the world is almost identical. We then made an AV-2 infectious clone by simultaneous inoculation with in vitro transcripts of RNAs 1-3 of AV-2 and in vitro-synthesized CP, which is necessary for initial infection. Because 2b of cucumoviruses in Bromoviridae can suppress systemic silencing as well as local silencing, we analyzed whether there is functional synteny of 2b between AV-2 and cucumovirus. Using the AV-2 infectious clone, we here provided first evidence that Ilarvirus 2b functions as an RNA silencing suppressor; AV-2 2b has suppressor activity against systemic silencing but not local silencing.

  13. The Ca2+ Antagonizing Effect of Chinese Cobra Venom Factor on Formation of Macrophage-derived Foam Cells

    Institute of Scientific and Technical Information of China (English)

    谭健苗; 杨向东; 姜志胜; 李亮

    2007-01-01

    Purpose CCVF was isolated from Chinese cobra (Naja naja) venom, its Ca2+ antagonizing effect on formation of macrophage-derived foam cells was explored in these studies. Methods Foam cell models were induced with C57BL/6J mouse peritoneal macrophages incubated in 10mg/L oxidized low density lipoprotein (OLDL), and their intracellular Ca2+ levels influenced both slowly and transiently by CCVF were determined with the technique of Ca2+ fluorescent indicator. Results The intracellular Ca2+ level with the macrophages incubated in 10mg/L OLDL and 10mg/L CCVF was 40.2% of the macrophages incubated in 10mg/L OLDL (P<0.05); While the transient influence of CCVF on the intracellular Ca2+ levels were not significant. Conclusion CCVF exerted a long-lasting antagonizing role on the enhancement of intracellular Ca2+ levels, thus inhibited the formation of macrophage-derived foam cell.

  14. Le silence, ce cri qui résonne dans l’écriture de Viviane Forrester

    Directory of Open Access Journals (Sweden)

    Amelia Peral Crespo

    2015-11-01

    Full Text Available The Holocaust Literature is tied to Silence from its beginning as the writing to silence. Write about the Holocaust and relate the experiences lived in first person or transmit them to the coming generations means leaving the silence which, for years, was the ideal refuge. This research focuses on the literary production of Viviane Forrester. The different expressions of silence that characterize her writings are analyzed. Silence is the cry that underlies in the most profound of the human being that return from the concentration camps, as Lazarus from the dead. It is a silence that grows to a cry because Forrester’s writing, almost in parallel to the fragmentary writing of Blanchot, an-nounces livre à venir, expressing the cry in silence without the ending of the word

  15. Evidence of pomegranate methanolic extract in antagonizing the endogenous SERM, 27-hydroxycholesterol.

    Science.gov (United States)

    Vini, Ravindran; Juberiya, Azeez M; Sreeja, Sreeharshan

    2016-02-01

    The direct relationship between obesity and breast cancer has been elucidated recently with the identification of a cholesterol derivative 27-hydroxycholesterol (27HC), an endogenous SERM that can act through estrogen receptor (ER)-mediated mechanisms. Our recent research shed light on the possible SERM-like property of methanol extract of pericarp of pomegranate (PME) by using human breast (MCF-7, MDA-MB-231), endometrial (HEC-1A), cervical (SiHa, HeLa), ovarian (SKOV3) cancer cell lines, normal breast fibroblasts (MCF-10A) and also by in vivo models (ovariectomized Swiss albino mice). Our findings demonstrated that PME binds to ER and downregulates the Estrogen response elements (ERE)-mediated transcription in breast cancer cells without being agonistic in the uterine endometrium and has cardioprotective effects comparable to that of 17-β-estradiol. This preliminary work indicates the ability of PME to antagonize the activity of 27HC. We hypothesize that PME can compete with 27HC for ERα and reduce 27HC-induced proliferation of MCF-7 cells. Relevant estrogen-regulated genes such as pS2, PR and ERα were checked to evaluate the ability of PME to abrogate 27HC-induced genes. This study is significant, being the first report describing that bioactive components of the methanolic extract of pericarp of PME, a proven SERM could plausibly compete for 27HC. PMID:26756990

  16. Synergism and antagonism in Iron base metallic glass corrosion inhibition by Thiosemicarbazone Compounds and Bromide Ions

    International Nuclear Information System (INIS)

    The synergistic and antagonism action caused by Br ions on the corrosion inhibition of fe78B13Si19 glassy alloy in 0.2 M Na2SO4 in absence and presence 10 (to power-4) M of some thiosemicarbazone derivatives have been investigated using potentiodynamic polarization, a.c. impedance techniques and morphological study. Results show that the addition of Br ions to sulphate solution inhibit the corrosion process by acting as an electron transfer barrier due to direct adsorption of these ions on alloy surface. A synergistic effect exists when fixed concentration of studied thiosemicarbazone derivatives and low concentration Br ions are used together to prevent glassy alloy corrosion in Na2SO4. The increase in surface coverage values in the presence at low concentrations Br ions indicates that an insoluble complex formed by undergoing a joint adsorption. The synergism parameter (S) is defined and calculated by the surface coverage values. The parameter in the case of small amount of Br found to be more than unity, indicating that the enhanced inhibition efficiency caused by the addition of Br ions is only due to synergism and there is a definite contribution from the inhibitor molecule. (author)

  17. Antagonism of Acute Sulfide Poisoning in Mice by Nitrite Anion without Methemoglobinemia.

    Science.gov (United States)

    Cronican, Andrea A; Frawley, Kristin L; Ahmed, Humza; Pearce, Linda L; Peterson, Jim

    2015-07-20

    There are currently no FDA-approved antidotes for H2S/sulfide intoxication. Sodium nitrite, if given prophylactically to Swiss Webster mice, was shown to be highly protective against the acute toxic effects of sodium hydrosulfide (∼LD40 dose) with both agents administered by intraperitoneal injections. However, sodium nitrite administered after the toxicant dose did not detectably ameliorate sulfide toxicity in this fast-delivery, single-shot experimental paradigm. Nitrite anion was shown to rapidly produce NO in the bloodstream, as judged by the appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin, together amounting to less than 5% of the total hemoglobin present. Sulfide-intoxicated mice were neither helped by the supplemental administration of 100% oxygen nor were there any detrimental effects. Compared to cyanide-intoxicated mice, animals surviving sulfide intoxication exhibited very short knockdown times (if any) and full recovery was extremely fast (∼15 min) irrespective of whether sodium nitrite was administered. Behavioral experiments testing the ability of mice to maintain balance on a rotating cylinder showed no motor impairment up to 24 h post sulfide exposure. It is argued that antagonism of sulfide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity of nitrite rather than formation of methemoglobin.

  18. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  19. E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Roberta L. [Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Wilkinson, John C., E-mail: john.wilkinson@ndsu.edu [Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Ornelles, David A., E-mail: ornelles@wakehealth.edu [Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States)

    2014-05-15

    Adenovirus inundates the productively infected cell with linear, double-stranded DNA and an abundance of single-stranded DNA. The cellular response to this stimulus is antagonized by the adenoviral E1B and E4 early genes. A mutant group C adenovirus that fails to express the E1B-55K and E4ORF3 genes is unable to suppress the DNA-damage response. Cells infected with this double-mutant virus display significant morphological heterogeneity at late times of infection and frequently contain fragmented nuclei. Nuclear fragmentation was due to the translocation of apoptosis inducing factor (AIF) from the mitochondria into the nucleus. The release of AIF was dependent on active poly(ADP-ribose) polymerase-1 (PARP-1), which appeared to be activated by viral DNA replication. Nuclear fragmentation did not occur in AIF-deficient cells or in cells treated with a PARP-1 inhibitor. The E1B-55K or E4ORF3 proteins independently prevented nuclear fragmentation subsequent to PARP-1 activation, possibly by altering the intracellular distribution of PAR-modified proteins. - Highlights: • E1B-55K or E4orf3 prevents nuclear fragmentation. • Nuclear fragmentation requires AIF and PARP-1 activity. • Adenovirus DNA replication activates PARP-1. • E1B-55K or E4orf3 proteins alter the distribution of PAR.

  20. Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus.

    Science.gov (United States)

    Zhao, Lan-Juan; He, Sheng-Fei; Wang, Wen; Ren, Hao; Qi, Zhong-Tian

    2016-04-01

    We aimed to investigate regulation of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) by interferon alpha (IFN-α) and to analyze the relationship between STAT3 and SOCS3 during hepatitis C virus (HCV) infection. Changes in STAT3 and SOCS3 were analyzed at both mRNA and protein levels in human hepatoma cells infected with HCV (J6/JFH1). At 72h of HCV infection, STAT3 expression was decreased with sustained phosphorylation, and IFN-α increased such decrease and phosphorylation. HCV increased SOCS3 expression, while IFN-α impaired such increase, indicating different regulation of STAT3 and SOCS3 by IFN-α. IFN-α-induced expression and phosphorylation of upstream kinases of the JAK/STAT pathway, Tyk2 and Jak1, were suppressed by HCV. Moreover, knockdown of STAT3 by RNA interference led to decreases in HCV RNA replication and viral protein expression, without affecting either the expression of Tyk2 and Jak1 or the SOCS3 induction in response to IFN-α. These results show that IFN-α antagonizes STAT3 and SOCS3 signaling triggered by HCV and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-α, which may be important in better understanding the complex interplay between IFN-α and signal molecules during HCV infection. PMID:26945996

  1. Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia

    Science.gov (United States)

    Machta, Benjamin B.; Gray, Ellyn; Nouri, Mariam; McCarthy, Nicola L. C.; Gray, Erin M.; Miller, Ann L.; Brooks, Nicholas J.; Veatch, Sarah L.

    2016-08-01

    Diverse molecules induce general anesthesia with potency strongly correlated both with their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol anesthetics inhibit heterogeneity in plasma membrane derived vesicles by lowering the critical temperature ($T_c$) for phase separation. Here we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n-alcohols and effects on $T_c$. First we show that hexadecanol acts oppositely to n-alcohol anesthetics on membrane mixing and antagonizes ethanol induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described `intoxication reversers' raise $T_c$ and counter ethanol's effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that hydrostatic pressure, long known to reverse anesthesia, also raises $T_c$ in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that $\\Delta T_c$ predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.

  2. ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization.

    Directory of Open Access Journals (Sweden)

    Misha I Kazi

    2016-04-01

    Full Text Available The virulence regulator ToxR initiates and coordinates gene expression needed by Vibrio cholerae to colonize the small intestine and cause disease. Despite its prominence in V. cholerae virulence, our understanding of the direct ToxR regulon is limited to four genes: toxT, ompT, ompU and ctxA. Here, we determine ToxR's genome-wide DNA-binding profile and demonstrate that ToxR is a global regulator of both progenitor genome-encoded genes and horizontally acquired islands that encode V. cholerae's major virulence factors and define pandemic lineages. We show that ToxR shares more than a third of its regulon with the histone-like nucleoid structuring protein H-NS, and antagonizes H-NS binding at shared binding locations. Importantly, we demonstrate that this regulatory interaction is the critical function of ToxR in V. cholerae colonization and biofilm formation. In the absence of H-NS, ToxR is no longer required for V. cholerae to colonize the infant mouse intestine or for robust biofilm formation. We further illustrate a dramatic difference in regulatory scope between ToxR and other prominent virulence regulators, despite similar predicted requirements for DNA binding. Our results suggest that factors in addition to primary DNA structure influence the ability of ToxR to recognize its target promoters.

  3. Antagonism and Molecular Identification of an Antibiotic Bacterium BS04 Against Phytopathogenic Fungi and Bacteria

    Institute of Scientific and Technical Information of China (English)

    Xie Jing(谢晶); Ge Shaorong; Tao Yong; Gao Ping; Liu Kun; Liu Shigui

    2004-01-01

    Through a modified agar well diffusion assay, antagonism of bacterium BS04 is tested. The data show that BS04 has antibiotic activity against phytopathogenic fungi and bacteria, including Phoma wasabiae Yokogi, Cochlibolus Heterostrophu, Exserohilum Turcicum, Curuvularia Lunata (Walk) Boed, Thantephorus cucumris, Fusarium graminearum, Xanthomonas axonopodis pv. Citri (Hasse) Dye and Xanthomonas zingiberi (Uyeda) Savulescu. The products of bacterium BS04 can endure the treatment of a wide range of pH, and maintain the antibiotic activity after treatment of 100℃ for 30 min. The result suggests that bacterium BS04 has the potential as a promising biocontrol agent. In order to determine the taxonomic placement, the molecular identification of BS04 is performed. The comparative analysis of 16s rDNA sequences indicates that the 16s rDNA sequence of BS04 is highly homologous with sequences of typical Paenibacillus bacteria from the RPD library (from 92% to 99%). And the constructed phylogenetic tree by using maximum-likelihood method with Bootstrap Trial 1000 proves that BS04 is subjected to Paenibacillus polymyxa.

  4. TRPV1 Antagonism by Capsazepine Modulates Innate Immune Response in Mice Infected with Plasmodium berghei ANKA

    Directory of Open Access Journals (Sweden)

    Elizabeth S. Fernandes

    2014-01-01

    Full Text Available Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host’s defence to malaria. Transient receptor potential vanilloid 1 (TRPV1 modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 105 red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80+Ly6G+ cell numbers as well as activation of both F4/80+and F4/80+Ly6G+ cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1+ and natural killer (NK population, without interfering with natural killer T (NKT cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.

  5. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  6. Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation.

    Science.gov (United States)

    Finsnes, F; Lyberg, T; Christensen, G; Skjønsberg, O H

    2001-04-01

    Endothelin (ET)-1 has been launched as an important mediator in bronchial asthma, which is an eosinophilic airway inflammation. However, the interplay between ET-1 and other proinflammatory mediators during the development of airway inflammation has not been elucidated. We wanted to study 1) whether the production of ET-1 precedes the production of other proinflammatory mediators and 2) whether ET-1 stimulates the production of these mediators within the airways. These hypotheses were studied during the development of an eosinophilic airway inflammation in rats. The increase in ET-1 mRNA level in lung tissue preceded the increase in mRNA levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-8. Treatment of the animals with the ET receptor antagonist bosentan resulted in a substantial decrease in the concentrations of tumor necrosis factor-alpha, IL-4, IL-1beta, interferon-gamma, and ET-1 in bronchoalveolar lavage fluid. In conclusion, the synthesis of ET-1 as measured by increased mRNA level precedes the synthesis of other proinflammatory cytokines of importance for the development of an eosinophilic airway inflammation, and ET antagonism inhibits the production of these mediators within the airways. Whether treatment with ET antagonists will prove beneficial for patients with eosinophilic airway inflammations like bronchial asthma is not yet known. PMID:11238005

  7. Plant Essential Oils Synergize and Antagonize Toxicity of Different Conventional Insecticides against Myzus persicae (Hemiptera: Aphididae.

    Directory of Open Access Journals (Sweden)

    Nicoletta Faraone

    Full Text Available Plant-derived products can play an important role in pest management programs. Essential oils from Lavandula angustifolia (lavender and Thymus vulgaris (thyme and their main constituents, linalool and thymol, respectively, were evaluated for insecticidal activity and synergistic action in combination with insecticides against green peach aphid, Myzus persicae (Sulzer (Hemiptera: Aphididae. The essential oils and their main constituents exerted similar insecticidal activity when aphids were exposed by direct sprays, but were non-toxic by exposure to treated leaf discs. In synergism experiments, the toxicity of imidacloprid was synergized 16- to 20-fold by L. angustifolia and T. vulgaris essential oils, but far less synergism occurred with linalool and thymol, indicating that secondary constituents of the oils were probably responsible for the observed synergism. In contrast to results with imidacloprid, the insecticidal activity of spirotetramat was antagonized by L. angustifolia and T. vulgaris essential oils, and linalool and thymol. Our results demonstrate the potential of plant essential oils as synergists of insecticides, but show that antagonistic action against certain insecticides may occur.

  8. Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation

    Institute of Scientific and Technical Information of China (English)

    Hai Jiang; Jianchun Wu; Chen He; Wending Yang; Honglin Li

    2009-01-01

    Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. (2007) found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kB signaling. We report here the identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdkl activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexpression. Intriguingly, we found that C53 interacts with Chkl and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.

  9. Resistin-binding peptide antagonizes role of resistin on white adipose tissue

    Institute of Scientific and Technical Information of China (English)

    Nan GU; Shu-ping HAN; Li FEI; Xiao-qin PAN; Mei GUO; Rong-hua CHEN; Xi-rong GUO

    2007-01-01

    Aim: To investigate the direct effects of resistin and resistin-binding peptide (RBP) on lipid metabolism and endocrine function in adipose tissue. Methods: Rat white adipose tissue was cultured in vitro and incubated for 24 h with 30 ng/Ml recombinant rat resistin protein (rResistin) or combined with RBP of varying concentrations(1x10-12 mol/L, 1x10-10mol/L, 1x10-8mol/L). Free fatty acids (FFA) released into medium was measured by a colorimetric kit. The levels of protein secretion and mRNA expression of TNF-α and adiponectin were detected by ELISA kit and RT-PCR respectively. Results: The levels of FFA released into medium were significantly increased after 24 h of exposure to rResistin, but significantly decreased after RBP was applied, although there was no difference between the 3 concentrations. The protein level and gene expression of TNF-α in adipose tissue were significantly increased after 24 h of exposure to rResistin, but only obviously decreased after incubated with Ix 10-8 mol/L RBP. The levels of protein secretion and mRNA expression of adiponectin in adipose tissue were significantly de-creased after 24 h of exposure to rResistin, but increased after incubated with RBP with the higher concentrations. Conclusion: RBP can effectively antagonize the role of resistin on the lipid metabolism and endocrine function of adipose tissue.

  10. Caffeine intake antagonizes salt sensitive hypertension through improvement of renal sodium handling.

    Science.gov (United States)

    Yu, Hao; Yang, Tao; Gao, Peng; Wei, Xing; Zhang, Hexuan; Xiong, Shiqiang; Lu, Zongshi; Li, Li; Wei, Xiao; Chen, Jing; Zhao, Yu; Arendshorst, William J; Shang, Qianhui; Liu, Daoyan; Zhu, Zhiming

    2016-01-01

    High salt intake is a major risk factor for hypertension. Although acute caffeine intake produces moderate diuresis and natriuresis, caffeine increases the blood pressure (BP) through activating sympathetic activity. However, the long-term effects of caffeine on urinary sodium excretion and blood pressure are rarely investigated. Here, we investigated whether chronic caffeine administration antagonizes salt sensitive hypertension by promoting urinary sodium excretion. Dahl salt-sensitive (Dahl-S) rats were fed with high salt diet with or without 0.1% caffeine in drinking water for 15 days. The BP, heart rate and locomotor activity of rats was analyzed and urinary sodium excretion was determined. The renal epithelial Na(+) channel (ENaC) expression and function were measured by in vivo and in vitro experiments. Chronic consumption of caffeine attenuates hypertension induced by high salt without affecting sympathetic nerve activity in Dahl-S rats. The renal α-ENaC expression and ENaC activity of rats decreased after chronic caffeine administration. Caffeine increased phosphorylation of AMPK and decrease α-ENaC expression in cortical collecting duct cells. Inhibiting AMPK abolished the effect of caffeine on α-ENaC. Chronic caffeine intake prevented the development of salt-sensitive hypertension through promoting urinary sodium excretion, which was associated with activation of renal AMPK and inhibition of renal tubular ENaC. PMID:27173481

  11. Innate immune restriction and antagonism of viral RNA lacking 2'-O methylation

    Energy Technology Data Exchange (ETDEWEB)

    Hyde, Jennifer L. [Departments of Medicine, Washington University School of Medicine, St Louis., MO 63110 (United States); Diamond, Michael S., E-mail: diamond@borcim.wustl.edu [Departments of Medicine, Washington University School of Medicine, St Louis., MO 63110 (United States); Molecular Microbiology, Washington University School of Medicine, St Louis., MO 63110 (United States); Pathology & Immunology, Washington University School of Medicine, St Louis., MO 63110 (United States); The Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis., MO 63110 (United States)

    2015-05-15

    N-7 and 2′-O methylation of host cell mRNA occurs in the nucleus and results in the generation of cap structures (cap 0, m{sup 7}GpppN; cap 1, m{sup 7}GpppNm) that control gene expression by modulating nuclear export, splicing, turnover, and protein synthesis. Remarkably, RNA cap modification also contributes to mammalian cell host defense as viral RNA lacking 2′-O methylation is sensed and inhibited by IFIT1, an interferon (IFN) stimulated gene (ISG). Accordingly, pathogenic viruses that replicate in the cytoplasm have evolved mechanisms to circumvent IFIT1 restriction and facilitate infection of mammalian cells. These include: (a) generating cap 1 structures on their RNA through cap-snatching or virally-encoded 2′-O methyltransferases, (b) using cap-independent means of translation, or (c) using RNA secondary structural motifs to antagonize IFIT1 binding. This review will discuss new insights as to how specific modifications at the 5′-end of viral RNA modulate host pathogen recognition responses to promote infection and disease.

  12. Innate immune restriction and antagonism of viral RNA lacking 2'-O methylation

    International Nuclear Information System (INIS)

    N-7 and 2′-O methylation of host cell mRNA occurs in the nucleus and results in the generation of cap structures (cap 0, m7GpppN; cap 1, m7GpppNm) that control gene expression by modulating nuclear export, splicing, turnover, and protein synthesis. Remarkably, RNA cap modification also contributes to mammalian cell host defense as viral RNA lacking 2′-O methylation is sensed and inhibited by IFIT1, an interferon (IFN) stimulated gene (ISG). Accordingly, pathogenic viruses that replicate in the cytoplasm have evolved mechanisms to circumvent IFIT1 restriction and facilitate infection of mammalian cells. These include: (a) generating cap 1 structures on their RNA through cap-snatching or virally-encoded 2′-O methyltransferases, (b) using cap-independent means of translation, or (c) using RNA secondary structural motifs to antagonize IFIT1 binding. This review will discuss new insights as to how specific modifications at the 5′-end of viral RNA modulate host pathogen recognition responses to promote infection and disease

  13. Prolongevity medicine: Antagonic-Stress drug in distress, geriatrics, and related diseases. II. Clinical review--2003.

    Science.gov (United States)

    Riga, S; Riga, D; Schneider, F

    2004-06-01

    Distress and senescence, their reciprocal aggravating-quickening connections, and their related pathologies have a large worldwide impact on healthcare systems in this new millennium. For this reason, Antagonic-Stress (AS)--an advanced integrative therapy, with specific synergistic composition, and patented internationally--represents a significant strategy in health, aging, and longevity. Clinical research with AS proves the drug's efficacy in the management of distress (neurotic, stress-related, and affective disorders; behavioral syndromes associated with physiological disturbances and physical factors; mental and behavioral disorders due to psychoactive substance uses) and psychogeriatrics [organic, including symptomatic, mental disorders (OMD)]. Specific multiaxial psychopathological instruments and psychometric tests in multiple assessments used for gerontopsychiatry demonstrated strong improvements after AS administration in early-moderate stages of Alzheimer or vascular dementia, as well as in other OMD. In addition, comparative clinical studies evinced the superiority of AS (synergistic multitherapy) versus monotherapy [meclofenoxate (MF), piracetam (PA), pyritinol (PT), and nicergoline (NE), respectively]. These comparative clinical trials agreed closely with comparative preclinical research and confirmed AS synergistic homeostatic, adaptogenic, antioxidative, cerebrovascular, neurometabolic, and nootropic actions. Also, the AS protective actions against oxidative stress recommend this orthomolecular therapy in stress, aging, and free radical pathology. PMID:15247054

  14. NPY antagonism reduces adiposity and attenuates age-related imbalance of adipose tissue metabolism.

    Science.gov (United States)

    Park, Seongjoon; Fujishita, Chika; Komatsu, Toshimitsu; Kim, Sang Eun; Chiba, Takuya; Mori, Ryoichi; Shimokawa, Isao

    2014-12-01

    An orexigenic hormone, neuropeptide Y (NPY), plays a role not only in the hypothalamic regulation of appetite, but also in the peripheral regulation of lipid metabolism. However, the intracellular mechanisms triggered by NPY to regulate lipid metabolism are poorly understood. Here we report that NPY deficiency reduces white adipose tissue (WAT) mass and ameliorates the age-related imbalance of adipose tissue metabolism in mice. Gene expression involved in adipogenesis/lipogenesis was found to decrease, whereas proteins involved in lipolysis increased in gonadal WAT (gWAT) of NPY-knockout mice. These changes were associated with an activated SIRT1- and PPARγ-mediated pathway. Moreover, the age-related decrease of de novo lipogenesis in gWAT and thermogenesis in inguinal WAT was inhibited by NPY deficiency. Further analysis using 3T3-L1 cells showed that NPY inhibited lipolysis through the Y1 receptor and enhanced lipogenesis following a reduction in cAMP response element-binding protein (CREB) and SIRT1 protein expression. Therefore, NPY appears to act as a key regulator of adipose tissue metabolism via the CREB-SIRT1 signaling pathway. Taken together, NPY deficiency reduces adiposity and ameliorates the age-related imbalance of adipose tissue metabolism, suggesting that antagonism of NPY may be a promising target for drug development to prevent age-related metabolic diseases.

  15. Continuous adenosine A2A receptor antagonism after focal cerebral ischemia in spontaneously hypertensive rats.

    Science.gov (United States)

    Fronz, Ulrike; Deten, Alexander; Baumann, Frank; Kranz, Alexander; Weidlich, Sarah; Härtig, Wolfgang; Nieber, Karen; Boltze, Johannes; Wagner, Daniel-Christoph

    2014-02-01

    Antagonism of the adenosine A2A receptor (A2AR) has been shown to elicit substantial neuroprotective properties when given immediately after cerebral ischemia. We asked whether the continuous application of a selective A2AR antagonist within a clinically relevant time window will be a feasible and effective approach to treat focal cerebral ischemia. To answer this question, we subjected 20 male spontaneously hypertensive rats to permanent middle cerebral artery occlusion and randomized them equally to a verum and a control group. Two hours after stroke onset, the animals received a subcutaneous implantation of an osmotic minipump filled with 5 mg kg(-1) day(-1) 8-(3-chlorostyryl) caffeine (CSC) or vehicle solution. The serum level of CSC was measured twice a day for three consecutive days. The infarct volume was determined at days 1 and 3 using magnetic resonance imaging. We found the serum level of CSC showing a bell-shaped curve with its maximum at 36 h. The infarct volume was not affected by continuous CSC treatment. These results suggest that delayed and continuous CSC application was not sufficient to treat acute ischemic stroke, potentially due to unfavorable hepatic elimination and metabolization of the pharmaceutical. PMID:24170241

  16. Glutathione and the Antioxidant Potential of Binary Mixtures with Flavonoids: Synergisms and Antagonisms

    Directory of Open Access Journals (Sweden)

    Patrícia Valentão

    2013-07-01

    Full Text Available Polyphenols are able to trap free radicals, which contributes to their known antioxidant capacity. In plant extracts, these secondary metabolites may act in concert, in a way that their combined activities will be superior to their individual effects (synergistic interaction. Several polyphenols have demonstrated clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. As so, the intake of these compounds at certain concentrations in the diet and/or supplementation may potentiate the activity of reduced form glutathione (GSH, thus better fighting oxidative stress. The aim of this work was to predict a structure-antioxidant activity relationship using different classes of flavonoids and to assess, for the first time, possible synergisms and antagonisms with GSH. For these purposes a screening microassay involving the scavenging of DPPH• was applied. In general, among the tested compounds, those lacking the catechol group in B ring showed antagonistic behaviour with GSH. Myricetin displayed additive effect, while quercetin, fisetin, luteolin, luteolin-7-O-glucoside, taxifolin and (+-catechin demonstrated synergistic actions. Furthermore, adducts formed at C2′ and C5′ of the B ring seem to be more important for the antioxidant capacity than adducts formed at C6 and C8 of the A ring.

  17. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.

    Science.gov (United States)

    Gérard, C; Blacher, S; Communal, L; Courtin, A; Tskitishvili, E; Mestdagt, M; Munaut, C; Noel, A; Gompel, A; Péqueux, C; Foidart, J M

    2015-01-01

    Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E2), E4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared with E2, E4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERα (ESR1) is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties toward the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation. PMID:25359896

  18. Salicylic acid antagonizes abscisic acid inhibition of shoot growth and cell cycle progression in rice

    Science.gov (United States)

    Meguro, Ayano; Sato, Yutaka

    2014-04-01

    We analysed effects of abscisic acid (ABA, a negative regulatory hormone), alone and in combination with positive or neutral hormones, including salicylic acid (SA), on rice growth and expression of cell cycle-related genes. ABA significantly inhibited shoot growth and induced expression of OsKRP4, OsKRP5, and OsKRP6. A yeast two-hybrid assay showed that OsKRP4, OsKRP5, and OsKRP6 interacted with OsCDKA;1 and/or OsCDKA;2. When SA was simultaneously supplied with ABA, the antagonistic effect of SA completely blocked ABA inhibition. SA also blocked ABA inhibition of DNA replication and thymidine incorporation in the shoot apical meristem. These results suggest that ABA arrests cell cycle progression by inducing expression of OsKRP4, OsKRP5, and OsKRP6, which inhibit the G1/S transition, and that SA antagonizes ABA by blocking expression of OsKRP genes.

  19. Bioethanol in Biofuels Checked by an Amperometric Organic Phase Enzyme Electrode (OPEE) Working in "Substrate Antagonism" Format.

    Science.gov (United States)

    Tomassetti, Mauro; Spuri Capesciotti, Gabriele; Angeloni, Riccardo; Martini, Elisabetta; Campanella, Luigi

    2016-01-01

    The bioethanol content of two samples of biofuels was determined directly, after simple dilution in decane, by means of an amperometric catalase enzyme biosensor working in the organic phase, based on substrate antagonisms format. The results were good from the point of view of accuracy, and satisfactory for what concerns the recovery test by the standard addition method. Limit of detection (LOD) was on the order of 2.5 × 10(-5) M. PMID:27571076

  20. Leptin Analog Antagonizes Leptin Effects on Food Intake and Body Weight but Mimics Leptin-Induced Vagal Afferent Activation

    OpenAIRE

    Peters, J H; Simasko, S. M.; Ritter, R. C.

    2007-01-01

    A recombinantly produced murine leptin analog (MLA) antagonizes leptin-induced signaling in cell lines that express the long form of the leptin receptor. However, the effects of MLA on the activity of leptin-sensitive neurons and on central neural controls of food intake have not been reported. Here we report effects of MLA on food intake and body weight in adult rats and on the activity of cultured rat vagal afferent neurons. Daily intracerebroventricular coinjection of MLA with exogenous le...

  1. Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism.

    Science.gov (United States)

    Rabella, Mireia; Grasa, Eva; Corripio, Iluminada; Romero, Sergio; Mañanas, Miquel Àngel; Antonijoan, Rosa M; Münte, Thomas F; Pérez, Víctor; Riba, Jordi

    2016-01-01

    •We assessed self-monitoring in schizotypal personality disorder (SPD) using ERPs.•SPD patients showed reduced amplitude of the error-related negativity (ERN).•Dopamine antagonism improved behavior and enhanced the ERN in patients only.•An inhibited ERN is a potential endophenotype of schizophrenia-spectrum disorders.•Results show impaired self-monitoring in SPD associated with dopamine disbalance.

  2. Controlling low frequency noise using a passive silencer

    Energy Technology Data Exchange (ETDEWEB)

    DeGagne, D.C.; Faszer, A.C. [Noise Solutions Inc., Calgary, AB (Canada)

    2009-07-01

    Nearly 85 per cent of all the oil and natural gas recovered in Canada comes from Alberta where noise emissions from energy facilities are regulated by the Energy Resources Conservation Board (ERCB) and the Alberta Utilities Commission (AUC) through Noise Control Directive D-038. Operators of energy facilities in Alberta must meet the Permissible Sound Level (PSL) established for industrial facilities that are established for receptor locations such as nearby residences. Despite efforts to manage noise, complaints from nearby residents continue to occur even if the facility is in compliance. This is because high and mid frequency components can decay or be absorbed by air and ground conditions leaving mostly low frequency noise (LFN) at the residence. This paper explored the significance of LFN and how some facility operators are dealing with this problem. The impacts of LFN can range from creating a sensation of pressure in the ear, disturbing normal conversation, to creating secondary vibrating effects within homes. If severe enough, it can also result in potential behavioural dysfunction such as task performance deterioration, sleep disturbance and headaches. In 2006, Noise Solutions Inc. was approached by Hunt Oil Company regarding the installation of a new compressor at their Caroline site. The proposal posed a serious noise problem for the community which requested that the new compressor unit be developed without any additional noise impact on the area. Noise Solutions Inc. used a multi-phased approach to develop the most effective LFN silencer using best practical technology and materials. In an effort to fully attenuate both the high frequency noise (dBA) and the low frequency noise (dBC) of the new compressor unit, Noise Solutions and Hunt Oil agreed that a significant level of sound-suppression would be necessary. The entire noise-suppression unit was specially designed to compensate for the sheer size of the compressor building. The first step to

  3. Toxicities of glyphosate- and cypermethrin-based pesticides are antagonic in the tenspotted livebearer fish (Cnesterodon decemmaculatus).

    Science.gov (United States)

    Brodeur, Julie Céline; Malpel, Solène; Anglesio, Ana Belén; Cristos, Diego; D'Andrea, María Florencia; Poliserpi, María Belén

    2016-07-01

    Although pesticide contamination of surface waters normally occurs in the form of mixtures, the toxicity and interactions displayed by such mixtures have been little characterized until now. The present study examined the interactions prevailing in equitoxic and non-equitoxic binary mixtures of formulations of glyphosate (Glifoglex(®)) and cypermethrin (Glextrin(®)) to the tenspotted livebearer (Cnesterodon decemmaculatus), a widely distributed South American fish. The following 96 h-LC50s were obtained when pesticide formulations were tested individually: Glifoglex(®) 41.4 and 53 mg ae glyphosate/L; Glextrin(®) 1.89 and 2.60 μg cypermethrin/L. Equitoxic and non-equitoxic mixtures were significantly antagonic in all combinations tested. The magnitude of the antagonism (factor by which toxicity differed from concentration addition) varied between 1.37 and 3.09 times in the different non-equitoxic mixtures tested. Antagonism was due to a strong inhibition of cypermethrin toxicity by the glyphosate formulation, the toxicity of the cypermethrin-based pesticide being almost completely overridden by the glyphosate formulation. Results obtained in the current study with fish are radically opposite to those previously observed in tadpoles where synergy was observed when Glifoglex(®) and Glextrin(®) were present in mixtures (Brodeur et al., 2014). PMID:27139121

  4. Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

    Directory of Open Access Journals (Sweden)

    Jennifer M. Monk

    2014-01-01

    Full Text Available During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA- derived eicosanoids, such as prostaglandin E2 (PGE2, promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS- induced colitis. Fat-1 mice contain the ω3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Δ5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, RORγτ, and IL-23, decreased percentages of Th17 cells and, improved colon injury scores (P≤0.05. Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

  5. A novel type of silencing factor, Clr2, is necessary for transcriptional silencing at various chromosomal locations in the fission yeast Schizosaccharomyces pombe

    DEFF Research Database (Denmark)

    Bjerling, Pernilla; Ekwall, Karl; Egel, Richard;

    2004-01-01

    of mammalian heterochromatin. Mutations in the swi6+, clr1+, clr2+, clr3+, clr4+ and clr6+ genes were obtained in screens for factors necessary for silencing the mat2-P-mat3-M region. swi6+ encodes a chromodomain protein, clr3+ and clr6+ histone deacetylases, and clr4+ a histone methyltransferase. Here, we...... describe the cloning and characterization of clr2+. The clr2+ gene encodes a 62 kDa protein with no obvious sequence homologs. Deletion of clr2+ not only affects transcriptional repression in the mating-type region, but also centromeric silencing and silencing of a PolII-transcribed gene inserted in the rDNA...

  6. Specific degradation of 3' regions of GUS mRNA in posttranscriptionally silenced tobacco lines may be related to 5'-3' spreading of silencing

    DEFF Research Database (Denmark)

    Braunstein, Thomas Hartig; Moury, Benoit; Johannessen, Marina;

    2002-01-01

    Target regions for posttranscriptional silencing of transgenes often reside in the 3' region of the coding sequence, although there are exceptions. To resolve if the target region is determined by the gene undergoing silencing rather than by the structure of the transgene loci or the plant genetic...... background, we have performed detailed analyses of target regions in three spontaneously beta-glucuronidase (GUS) silencing tobacco lines of different origin. From quantitative cosuppression experiments, we show that the main target region in all three tobacco lines is found within the 3' half of the GUS...... coding region but upstream of the last 200 nt. The quantities of small (21-25 nt) RNAs homologous to 5' or 3' regions of the GUS coding sequence were found to correlate approximately with the target strength of the corresponding regions. These results suggest that transgene locus structure and plant...

  7. A viral suppressor protein inhibits host RNA silencing by hooking up with Argonautes

    KAUST Repository

    Jin, Hailing

    2010-05-01

    RNA viruses are particularly vulnerable to RNAi-based defenses in the host, and thus have evolved specific proteins, known as viral suppressors of RNA silencing (VSRs), as a counterdefense. In this issue of Genes & Development, Azevedo and colleagues (pp. 904-915) discovered that P38, the VSR of Turnip crinkle virus, uses its glycine/tryptophane (GW) motifs as an ARGONAUTE (AGO) hook to attract and disarm the host\\'s essential effector of RNA silencing. Several GW motif-containing cellular proteins are known to be important partners of AGOs in RNA silencing effector complexes in yeast, plants, and animals. The GW motif appears to be a versatile and effective tool for regulating the activities of RNA silencing pathways, and the use of GW mimicry to compete for and inhibit host AGOs may be a strategy used by many pathogens to counteract host RNAi-based defenses. © 2010 by Cold Spring Harbor Laboratory Press.

  8. Identifying Silence Climate in Organizations in the Framework of Contemporary Management Approaches

    Directory of Open Access Journals (Sweden)

    Mustafa Emre Civelek

    2015-12-01

    Full Text Available Dynamic competition conditions in present day bring about the consequence for businesses to face varied problems with each passing day. At this point, current management approaches include studies that would shed light on the new problems of businesses. Organizational Silence, a concept that has recently been being voiced in business world, has come up in such context. Organizational silence could be expressed as the employee behavior of keeping silent about certain negativities due to various reasons in an organization. Since knowledge sharing in modern organizations is of capital importance in terms of responding hastily to the changes in a competitive environment, spread of this behavior of employees to organization culture and climate presents a threat of indifference. In this study, the concept of Organizational Silence is defined and the effects of conceived silence climate on management of organizations are discussed.

  9. Identifying Silence Climate in Organizations in the Framework of Contemporary Management Approaches

    Directory of Open Access Journals (Sweden)

    Mustafa Emre Civelek

    2015-10-01

    Full Text Available Dynamic competition conditions in present day, bring about the consequence for businesses to face varied problems with each passing day. At this point, current management approaches include studies that would shed light on the new problems of businesses. Organizational Silence, a concept that has recently been being voiced in business world, has come up in such context. Organizational silence could be expressed as the employee behavior of keeping silent about certain negativities due to various reasons in an organization. Since knowledge sharing in modern organizations is of capital importance in terms of responding hastily to the changes in a competitive environment, spread of this behavior of employees to organization culture and climate presents a threat of indifference. In this study, the concept of Organizational Silence is defined and the effects of conceived silence climate on management of organizations are discussed.

  10. REDUCTION OF NOISE OF ENVIRONMENTAL POLLUTION BY INSTALLING SILENCERS

    Directory of Open Access Journals (Sweden)

    Gorin V. A.

    2016-05-01

    Full Text Available The article describes the sources of noise Yeisk thermal power plant (TPP in excess of the permissible sound pressure levels in homes on the street. Gorky, 25. Eisk TPP is located near the residential area, where the permissible noise level standards adopted much more stringent than in the power plants. Prolonged exposure to noise leads to human disease noise disease. The scheme of movement of exhaust gases from the thermal power plant generating units Yeisk. Analysis of measurements of noise characteristics of main and auxiliary equipment showed that one of the main sources are sectioned estuaries double-barrel pipe height of 27 m and slices estuaries pipes emergency explosive valves flues installed on the roof at a height of 17 m. The previous Noise reduction nozzles that emit noise uniformly in all directions are replaced by advanced, whose index changed direction estuaries sections double-barrel tubes. This will change the level of radiated noise in residential development. If you change the angle of orientation of 135°-180°, the noise level in residential construction decreased by 7-10 dB. Shows a photograph of thermal power plants, residential buildings, the old and improved silencers

  11. Powerful Silences: Becoming a Survivor Through the Construction of Story

    Directory of Open Access Journals (Sweden)

    Arlene Voski Avakian

    2006-09-01

    Full Text Available Survivors’ accounts of traumatic events function on many levels for both the teller and the hearer. By giving voice to what has been silenced, testimonies to the lived experience of trauma challenge dominant perspectives on the meaning and significance of both historical and contemporary events. The construction of these stories and their telling may also provide a means of countering the devastating psychological effects of the trauma. This paper will explore one story about the Turkish genocide of Armenians in 1915 as told to me by my grandmother, Elmas Tutuian. Remarkably consistent over the years of its telling, Tutuian’s story omits as much as it tells. Examining this narrative from both a psychological and a textual perspective, I suggest that by choosing to be silent about parts of her experience, Tutuian constructed herself as a survivor rather than a victim. In choosing to tell her narrative to me, she also shaped my sense of resistance to oppression. The article references works analyzing survivors’ accounts of trauma from a literary, psychological, sociological, theological, and historical perspective.

  12. Senataxin controls meiotic silencing through ATR activation and chromatin remodeling.

    Science.gov (United States)

    Yeo, Abrey J; Becherel, Olivier J; Luff, John E; Graham, Mark E; Richard, Derek; Lavin, Martin F

    2015-01-01

    Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA-DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx (-/-) pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration. PMID:27462424

  13. Silencing structural and nonstructural genes in baculovirus by RNA interference.

    Science.gov (United States)

    Flores-Jasso, C Fabian; Valdes, Victor Julian; Sampieri, Alicia; Valadez-Graham, Viviana; Recillas-Targa, Felix; Vaca, Luis

    2004-06-01

    We review several aspects of RNAi and gene silencing with baculovirus. We show that the potency of RNAi in Spodoptera frugiperda (Sf21) insect cells correlates well with the efficiency of transfection of the siRNA. Using a fluorescein-labeled siRNA we found that the siRNA localized in areas surrounding the endoplasmic reticulum (ER). Both long (700 nucleotides long) and small ( approximately 25 nucleotides long) interfering RNAs were equally effective in initiating RNA interference (RNAi), and the duration of the interfering effect was indistinguishable. Even though RNAi in Sf21 cells is very effective, in vitro experiments show that these cells fragment the long dsRNA into siRNA poorly, when compared to HEK cells. Finally, we show that in vivo inhibition of baculovirus infection with dsRNA homologous to genes that are essential for baculovirus infectivity depends strongly on the amount of dsRNA used in the assays. Five hundred nanogram of dsRNA directly injected into the haemolymph of insects prevent animal death to over 95%. In control experiments, over 96% of insects not injected with dsRNA or injected with an irrelevant dsRNA died within a week. These results demonstrate the efficiency of dsRNA for in vivo prevention of a viral infection by virus that is very cytotoxic and lytic in animals.

  14. Silencing of DELLA induces facultative parthenocarpy in tomato fruits.

    Science.gov (United States)

    Martí, Cristina; Orzáez, Diego; Ellul, Philippe; Moreno, Vicente; Carbonell, Juan; Granell, Antonio

    2007-12-01

    DELLA proteins are plant nuclear factors that restrain growth and proliferation in response to hormonal signals. The effects of the manipulation of the DELLA pathway in the making of a berry-like fruit were investigated. The expression of the Arabidopsis thaliana gain-of-function DELLA allele Atgai (del) in tomato (Solanum lycopersicum L.) produced partially sterile dwarf plants and compacted influorescences, as expected for a constitutively activated growth repressor. In contrast, antisense silencing of the single endogenous tomato DELLA gene homologue (SlDELLA) produced slender-like plants with elongated flower trusses. Interestingly, the depletion of SlDELLA in tomato was sufficient to overcome the growth arrest normally imposed on the ovary at anthesis, resulting in parthenocarpic fruits in the absence of pollination. Antisense SlDELLA-engineered fruits were smaller in size and elongated in shape compared with wild type. Cell number estimations showed that fruit set, resulting from reduced SlDELLA expression, arose from activated cell elongation at the longitudinal and lateral axes of the fruit pericarp, bypassing phase-II (post-pollination) cell divisions. Parthenocarpy caused by SlDELLA depletion is facultative, as hand pollination restored wild-type fruit phenotype. This indicates that fertilization-associated SlDELLA-independent signals are operational in ovary-fruit transitions. SlDELLA was also found to restrain growth in other reproductive structures, affecting style elongation, stylar hair primordial growth and stigma development. PMID:17883372

  15. Evaluation of shRNA-mediated gene silencing by electroporation in LPB fibrosarcoma cells:

    OpenAIRE

    Čemažar, Maja; Kamenšek, Urška; Vidic, Suzana

    2008-01-01

    Background. Silencing oncogenes or other genes that contribute to tumor malignancy and progression offers a promising approach to treating cancer. Specific and efficient silencing of gene expression can be achieved by RNA interference (RNAi) technology using small interfering RNA (siRNA) or short hairpin RNA (shRNA). However, a major challenge in RNAi technology is effective delivery of interfering molecules into target cells. The aim of our study was to evaluate electroporation as a perspect...

  16. Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA

    OpenAIRE

    Orzalli, Megan H.; Conwell, Sara E.; Berrios, Christian; DeCaprio, James A.; Knipe, David M.

    2013-01-01

    Cells have evolved mechanisms to silence foreign DNA to prevent the expression of foreign genes within them. In mammalian cells, this involves the assembly of heterochromatin on foreign DNAs such as viral or transfected DNA. Herpesviruses have evolved strategies to counteract these host mechanisms to express their own genes. Herein we demonstrate that the nuclear DNA sensor IFN-inducible protein 16 (IFI16) is involved in the host silencing response to foreign DNA. IFI16 promotes the assembly ...

  17. Feasibility Study and Conception of an Intelligent GSM Cell Phone Silencer

    OpenAIRE

    Gorce, Jean-Marie; Kléber, Anja; Valois, Fabrice

    2002-01-01

    The European regulatory authorities are about to change the laws that deal with the proscription of cell phone silencers, towards the acceptance of intelligent systems. This technical report describes a cell phone silencer concept based on the idea of changing the access control parameters on the channel BCCH and develops other intelligent methods, also based on changing parameters on the common downlink channels. Intelligent in the way that they hamper people from using their cellular phones...

  18. Genetically encoded molecular tools for light-driven silencing of targeted neurons

    OpenAIRE

    Chow, Brian Y.; Han, Xue; Boyden, Edward S.

    2012-01-01

    The ability to silence, in a temporally precise fashion, the electrical activity of specific neurons embedded within intact brain tissue, is important for understanding the role that those neurons play in behaviors, brain disorders, and neural computations. “Optogenetic” silencers, genetically encoded molecules that, when expressed in targeted cells within neural networks, enable their electrical activity to be quieted in response to pulses of light, are enabling these kinds of causal circuit...

  19. Specific Tandem Repeats Are Sufficient for Paramutation-Induced Trans-Generational Silencing

    OpenAIRE

    Belele, Christiane L.; Lyudmila Sidorenko; Maike Stam; Rechien Bader; Arteaga-Vazquez, Mario A.; Chandler, Vicki L.

    2013-01-01

    Paramutation is a well-studied epigenetic phenomenon in which trans communication between two different alleles leads to meiotically heritable transcriptional silencing of one of the alleles. Paramutation at the b1 locus involves RNA-mediated transcriptional silencing and requires specific tandem repeats that generate siRNAs. This study addressed three important questions: 1) are the tandem repeats sufficient for paramutation, 2) do they need to be in an allelic position to mediate paramutati...

  20. Reconceptualising the right of silence as an effective fair trial standard

    OpenAIRE

    JACKSON, JOHN

    2009-01-01

    As the European Court of Human Rights has come to qualify the privilege against self-incrimination and the right of silence in recent decisions, this article argues that the Court has failed to provide a convincing rationale for these rights. It is claimed that within the criminal process the right of silence should be distinguished from the privilege against self-incrimination and given enhanced effect in order to uphold the protective and participatory rights of the defence which come into ...

  1. The Effect of Organizational Stress on Organizational Silence: An Application in Five Star Thermal Hotel Establishments

    OpenAIRE

    KILIÇ, Gonca; TUNÇ, Tülin; SARAÇLI, Sinan; KILIÇ, İbrahim

    2013-01-01

    In this study it was aimed to determine the effects of organizational stress on organizational silence with an application at five-stars hotel establishments and to review general literature on organizational stress and organizational silence. Study questionnaires were distributed 387 participants working at five-stars hotel establishments in Afyonkarahisar. Data was analyzed by factor analysis, reliability analysis, mean, standard deviation, Pearson’s correlation analysis, and bivariate ...

  2. Fast silencing reveals a lost role for reciprocal inhibition in locomotion

    OpenAIRE

    Moult, Peter Robert; Cottrell, Glen Alfred; Li, Wenchang

    2013-01-01

    Summary Alternating contractions of antagonistic muscle groups during locomotion are generated by spinal “half-center” networks coupled in antiphase by reciprocal inhibition. It is widely thought that reciprocal inhibition only coordinates the activity of these muscles. We have devised two methods to rapidly and selectively silence neurons on just one side of Xenopus tadpole spinal cord and hindbrain, which generate swimming rhythms. Silencing activity on one side led to rapid cessation of ac...

  3. Silencing of the rotavirus NSP4 protein decreases the incidence of biliary atresia in murine model.

    Directory of Open Access Journals (Sweden)

    Jiexiong Feng

    Full Text Available Biliary atresia is a common disease in neonates which causes obstructive jaundice and progressive hepatic fibrosis. Our previous studies indicate that rotavirus infection is an initiator in the pathogenesis of experimental biliary atresia (BA through the induction of increased nuclear factor-kappaB and abnormal activation of the osteopontin inflammation pathway. In the setting of rotavirus infection, rotavirus nonstructural protein 4 (NSP4 serves as an important immunogen, viral protein 7 (VP7 is necessary in rotavirus maturity and viral protein 4 (VP4 is a virulence determiner. The purpose of the current study is to clarify the roles of NSP4, VP7 and VP4 in the pathogenesis of experimental BA. Primary cultured extrahepatic biliary epithelia were infected with Rotavirus (mmu18006. Small interfering RNA targeting NSP4, VP7 or VP4 was transfected before rotavirus infection both in vitro and in vivo. We analyzed the incidence of BA, morphological change, morphogenesis of viral particles and viral mRNA and protein expression. The in vitro experiments showed NSP4 silencing decreased the levels of VP7 and VP4, reduced viral particles and decreased cytopathic effect. NSP4-positive cells had strongly positive expression of integrin subunit α2. Silencing of VP7 or VP4 partially decreased epithelial injury. Animal experiments indicated after NSP4 silencing, mouse pups had lower incidence of BA than after VP7 or VP4 silencing. However, 33.3% of VP4-silenced pups (N = 6 suffered BA and 50% of pups (N = 6 suffered biliary injury after VP7 silencing. Hepatic injury was decreased after NSP4 or VP4 silencing. Neither VP4 nor VP7 were detected in the biliary ducts after NSP4. All together, NSP4 silencing down-regulates VP7 and VP4, resulting in decreased incidence of BA.

  4. Efficiency for Gene Silencing Induction in Nicotiana Species by a Viral Satellite DNA Vector

    Institute of Scientific and Technical Information of China (English)

    You-Ping Xu; Lu-Ping Zheng; Qiu-Fang Xu; Chang-Chun Wang; Xue-Ping Zhou; Zu-Jian Wu; Xin-Zhong Cai

    2007-01-01

    Virus-induced gene silencing (VIGS) is a useful technique for rapid plant gene function analysis.We recently reported a new VIGS vector modified from Tomato yellow leaf curl China virus (TYLCCNV) DNAβ (DNAm β).In this study we compared In detail DNAmβ-induced gene silencing in four Nicotiana species including N.benthamiana, N.glutinosa, N.tabacum and N.paniculata.We found that DNAmβ-induced gene silencing in the four species was distinct in developing dynamics, tissue specificity, efficiency, and constancy in the plant life span.It was most efficient in N.benthamiana, where development of VIGS was most rapid, without tissue specificity and nearly 100% efficient.DNAmβ-induced gene silencing in N.Glutinosa was also efficient despite being slightly less than in N.benthamiana.It initially occurred in veins, later was scattered to mesophyll, finally led to complete silencing in whole leaves.In both species, VIGS constantly expressed until the plants died.However, DNAmβ-mediated VIGS in the other two Nicotiana species, N.tabacum and N.paniculata, was significantly less efficient.It was strictly limited within the veins of the silenced leaves, and constantly occurred only over 3-4 weeks.The upper leaves that emerged later stopped showing the silencing phenotype, DNAm β-induced gene silencing in N.benthamiana and N.glutinosa was not significantly influenced by the growth stage when the plants were agro-inoculated,and was not sensitive to high growth temperature up to 32℃, Our results indicate that this system has great potential as a versatile VIGS system for routine functional analysis of genes in some Nicotiana species.

  5. A viral suppressor protein inhibits host RNA silencing by hooking up with Argonautes

    OpenAIRE

    Jin, Hailing; Zhu, Jian-Kang

    2010-01-01

    RNA viruses are particularly vulnerable to RNAi-based defenses in the host, and thus have evolved specific proteins, known as viral suppressors of RNA silencing (VSRs), as a counterdefense. In this issue of Genes & Development, Azevedo and colleagues (pp. 904–915) discovered that P38, the VSR of Turnip crinkle virus, uses its glycine/tryptophane (GW) motifs as an ARGONAUTE (AGO) hook to attract and disarm the host's essential effector of RNA silencing. Several GW motif-containing cellular pro...

  6. Tailor: a computational framework for detecting non-templated tailing of small silencing RNAs

    OpenAIRE

    Chou, Min-Te; Han, Bo W; Hsiao, Chiung-Po; Phillip D Zamore; Weng, Zhiping; Hung, Jui-Hung

    2015-01-01

    Small silencing RNAs, including microRNAs, endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs), have been shown to play important roles in fine-tuning gene expression, defending virus and controlling transposons. Loss of small silencing RNAs or components in their pathways often leads to severe developmental defects, including lethality and sterility. Recently, non-templated addition of nucleotides to the 3′ end, namely tailing, was found to associate with the p...

  7. Gene Silencing and Polycomb Group Proteins: An Overview of their Structure, Mechanisms and Phylogenetics

    OpenAIRE

    Golbabapour, Shahram; Majid, Nazia Abdul; Hassandarvish, Pouya; Hajrezaie, Maryam; Abdulla, Mahmood Ameen; Hadi, A. Hamid A.

    2013-01-01

    DNA methylation, histone modifications, and chromatin configuration are crucially important in the regulation of gene expression. Among these epigenetic mechanisms, silencing the expression of certain genes depending on developmental stage and tissue specificity is a key repressive system in genome programming. Polycomb (Pc) proteins play roles in gene silencing through different mechanisms. These proteins act in complexes and govern the histone methylation profiles of a large number of genes...

  8. ANTAGONISM OF A. VIRIDANS TO CONDITIONALLY - PATHOGENIC MICROFLORA OF THE NOSE AND OROPHARYNX OF CHILDREN WITH CARDIAC PATOLOGY

    Directory of Open Access Journals (Sweden)

    Stepansky D.O.

    2015-12-01

    Full Text Available Introduction. Search for harmless and simultaneously effective probiotics, which could be successfully used for treatment and prevention of infectious deseases, is currently important. A. viridans is of particular interest, as it is representative of the normal microflora of human with broad spectrum of antibacterial action. The use of this microorganism has a number of advantages: the absence of side effects on the body; high adhesive abilities; resistance to lysozyme in saliva; the ability of use in patients, sensitized to antibiotics and chemotherapeutic drugs; stimulation effects on the human immune system. Material and methods. The purpose of the study was to investigate the antagonism of A. viridans № 167 and autostrains of aerococcuses, isolated at patients, to conditionally - pathogenic microflora of the nose and oropharynx of children with cardiac patology. At the first stage of the study the microflora of the of the nose and oropharynx of 2 investigated categories was examined – 40 children 4-14 years with cardiac patology and 40 healthy children 4-5 years old. The second stage of work was to study the effect of A. viridans on the explored strains. Results and discussion. A. viridans manifests the antagonism to all studied strains of gram-positive and gram-negative microorganisms, except C. albisans. A. viridans antagonistic activity to staphylococci (10 + 3 mm and streptococci (10 + 2mm is at the approximately same level. It is interesting to compare the antagonism of aerococcuses to clinical isolates of S. pyogenes and similar strains from carriers (healthy children category. Impact of aerococcuses on P. mirabilis strain appeared at the highest level. Autosimbionts of A. viridans, isolated from healthy children, are more antagonistic to CPM strains, isolated from these children, than autostrains of A. viridans, isolated from children with with cardiac patology, and higher than the museum strain of A. viridans № 167 antagonism

  9. The molecular basis for stability of heterochromatin-mediated silencing in mammals

    Directory of Open Access Journals (Sweden)

    Hiragami-Hamada Kyoko

    2009-11-01

    Full Text Available Abstract The archetypal epigenetic phenomenon of position effect variegation (PEV in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3, DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac and lysine 4 di or tri methylation (H3K4me2/3 are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.

  10. Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH.

    Science.gov (United States)

    El-Gaby, Mohamady; Zhang, Yu; Wolf, Konstantin; Schwiening, Christof J; Paulsen, Ole; Shipton, Olivia A

    2016-08-23

    Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals. PMID:27524609

  11. Efficient gene silencing by delivery of locked nucleic acid antisense oligonucleotides, unassisted by transfection reagents.

    Science.gov (United States)

    Stein, C A; Hansen, J Bo; Lai, Johnathan; Wu, SiJian; Voskresenskiy, Anatoliy; Høg, Anja; Worm, Jesper; Hedtjärn, Maj; Souleimanian, Naira; Miller, Paul; Soifer, Harris S; Castanotto, Daniella; Benimetskaya, Luba; Ørum, Henrik; Koch, Troels

    2010-01-01

    For the past 15-20 years, the intracellular delivery and silencing activity of oligodeoxynucleotides have been essentially completely dependent on the use of a delivery technology (e.g. lipofection). We have developed a method (called 'gymnosis') that does not require the use of any transfection reagent or any additives to serum whatsoever, but rather takes advantage of the normal growth properties of cells in tissue culture in order to promote productive oligonucleotide uptake. This robust method permits the sequence-specific silencing of multiple targets in a large number of cell types in tissue culture, both at the protein and mRNA level, at concentrations in the low micromolar range. Optimum results were obtained with locked nucleic acid (LNA) phosphorothioate gap-mers. By appropriate manipulation of oligonucleotide dosing, this silencing can be continuously maintained with little or no toxicity for >240 days. High levels of oligonucleotide in the cell nucleus are not a requirement for gene silencing, contrary to long accepted dogma. In addition, gymnotic delivery can efficiently deliver oligonucleotides to suspension cells that are known to be very difficult to transfect. Finally, the pattern of gene silencing of in vitro gymnotically delivered oligonucleotides correlates particularly well with in vivo silencing. The establishment of this link is of particular significance to those in the academic research and drug discovery and development communities.

  12. Post-transcriptional gene silencing signal could move rapidly and bidirectionally in grafted Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    LI Ming; JIANG Shiling; WANG Youqun; LIU Guoqin

    2006-01-01

    RNA interference (RNAi), one of the newly found ways for post-transcriptional gene silencing, has been widely used to investigate gene functions through transgenic methods for introducing an RNA silencing signal into plants. In the present study, we constructed a dexamethazone (DEX)-inducible RNAi binary vector harboring a specific sequence fragment (168-bp) homologous to KatB and KatC, two kinesin isoform genes of Arabidopsis, which were proved to result in the post-transcriptional gene silencing of KatB and KatC in DEX-induced transgenic plants. RT-PCR and Northern blot analysis on transgenic homozygous Arabidopsis (termed as RNAi-type plants) showed that DEX inducement causes KatB and KatC mRNA degradation. With a simplified method, Arabidopsis grafting was effectively performed between RNAi-type and wild-type lines. The target gene mRNA levels were tested based on semi-quantitative RT-PCR. Our results demonstrateed that DEX-induced gene silencing signals could result in a reduction in KatB and KatC mRNA in the wild-type rootstocks or scions, indicating that silencing signals of RNAi could be transmitted bidirectionally across the graft junction whether RNAi-plants were scions or stocks. In contrast to the previously reported results on grafted tobacco, the transmission of post- transcriptional gene silencing signals caused by RNAi in grafted Arabidopsis is more effective than that in tobacco.

  13. Strategy of gene silencing in cassava for validation of resistance genes

    International Nuclear Information System (INIS)

    Cassava (Manihot esculenta) is a major source of food for more than 1000 million people in the world and constitutes an important staple crop. Cassava bacterial blight, caused by the gram negative bacterium Xanthomonas axonopodis pv. manihotis, is one of the most important constraints for this crop. A candidate resistance gene against cassava bacterial blight, named RXam1, has been identified previously. In this work, we employed the gene silencing approach using the African cassava mosaic virus (ACMV) to validate the function of the RXam1 gene. We used as positive control the su gen, which produce photo blanching in leaves when is silenced. Plants from the SG10735 variety were bombardment with the ACMV-A-SU+ACMV-B y ACMV-A-RXam1+ACMV-B constructions. The silencing efficiency employing the su gene was low, only one of seven plants showed photo blanching. In the putative silenced plants for the RXam1 gene, no presence of siRNAs corresponding to RXam1 was observed; although a low diminution of the RXam1 gene expression was obtained. The growth curves for the Xam strain CIO136 in cassava plants inoculated showing a little but no significance difference in the susceptibility in the silenced plants compared to not silenced

  14. Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH

    Directory of Open Access Journals (Sweden)

    Mohamady El-Gaby

    2016-08-01

    Full Text Available Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals.

  15. Antagonism of CD11b with neutrophil inhibitory factor (NIF inhibits vascular lesions in diabetic retinopathy.

    Directory of Open Access Journals (Sweden)

    Alexander A Veenstra

    Full Text Available Leukocytes and proteins that govern leukocyte adhesion to endothelial cells play a causal role in retinal abnormalities characteristic of the early stages of diabetic retinopathy, including diabetes-induced degeneration of retinal capillaries. Leukocyte integrin αmβ2 (CD11b/CD18, MAC1, a protein mediating adhesion, has been shown to mediate damage to endothelial cells by activated leukocytes in vitro. We hypothesized that Neutrophil Inhibitory Factor (NIF, a selective antagonist of integrin αmβ2, would inhibit the diabetes-induced degeneration of retinal capillaries by inhibiting the excessive interaction between leukocytes and retinal endothelial cells in diabetes. Wild type animals and transgenic animals expressing NIF were made diabetic with streptozotocin and assessed for diabetes-induced retinal vascular abnormalities and leukocyte activation. To assess if the leukocyte blocking therapy compromised the immune system, animals were challenged with bacteria. Retinal superoxide production, leukostasis and leukocyte superoxide production were increased in wild type mice diabetic for 10 weeks, as was the ability of leukocytes isolated from diabetic animals to kill retinal endothelial cells in vitro. Retinal capillary degeneration was significantly increased in wild type mice diabetic 40 weeks. In contrast, mice expressing NIF did not develop any of these abnormalities, with the exception that non-diabetic and diabetic mice expressing NIF generated greater amounts of superoxide than did similar mice not expressing NIF. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge, suggesting that NIF did not compromise immune surveillance. We conclude that antagonism of CD11b (integrin αmβ2 by NIF is sufficient to inhibit early stages of diabetic retinopathy, while not compromising the basic immune response.

  16. Antagonism of CD11b with neutrophil inhibitory factor (NIF) inhibits vascular lesions in diabetic retinopathy.

    Science.gov (United States)

    Veenstra, Alexander A; Tang, Jie; Kern, Timothy S

    2013-01-01

    Leukocytes and proteins that govern leukocyte adhesion to endothelial cells play a causal role in retinal abnormalities characteristic of the early stages of diabetic retinopathy, including diabetes-induced degeneration of retinal capillaries. Leukocyte integrin αmβ2 (CD11b/CD18, MAC1), a protein mediating adhesion, has been shown to mediate damage to endothelial cells by activated leukocytes in vitro. We hypothesized that Neutrophil Inhibitory Factor (NIF), a selective antagonist of integrin αmβ2, would inhibit the diabetes-induced degeneration of retinal capillaries by inhibiting the excessive interaction between leukocytes and retinal endothelial cells in diabetes. Wild type animals and transgenic animals expressing NIF were made diabetic with streptozotocin and assessed for diabetes-induced retinal vascular abnormalities and leukocyte activation. To assess if the leukocyte blocking therapy compromised the immune system, animals were challenged with bacteria. Retinal superoxide production, leukostasis and leukocyte superoxide production were increased in wild type mice diabetic for 10 weeks, as was the ability of leukocytes isolated from diabetic animals to kill retinal endothelial cells in vitro. Retinal capillary degeneration was significantly increased in wild type mice diabetic 40 weeks. In contrast, mice expressing NIF did not develop any of these abnormalities, with the exception that non-diabetic and diabetic mice expressing NIF generated greater amounts of superoxide than did similar mice not expressing NIF. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge, suggesting that NIF did not compromise immune surveillance. We conclude that antagonism of CD11b (integrin αmβ2) by NIF is sufficient to inhibit early stages of diabetic retinopathy, while not compromising the basic immune response.

  17. A modeling and simulation study of siderophore mediated antagonism in dual-species biofilms

    Directory of Open Access Journals (Sweden)

    Collinson Shannon

    2009-12-01

    Full Text Available Abstract Background Several bacterial species possess chelation mechanisms that allow them to scavenge iron from the environment under conditions of limitation. To this end they produce siderophores that bind the iron and make it available to the cells later on, while rendering it unavailable to other organisms. The phenomenon of siderophore mediated antagonism has been studied to some extent for suspended populations where it was found that the chelation ability provides a growth advantage over species that do not have this possibility. However, most bacteria live in biofilm communities. In particular Pseudomonas fluorescens and Pseudomonas putida, the species that have been used in most experimental studies of the phenomenon, are known to be prolific biofilm formers, but only very few experimental studies of iron chelation have been published to date for the biofilm setting. We address this question in the present study. Methods Based on a previously introduced model of iron chelation and an existing model of biofilm growth we formulate a model for iron chelation and competition in dual species biofilms. This leads to a highly nonlinear system of partial differential equations which is studied in computer simulation experiments. Conclusions (i Siderophore production can give a growth advantage also in the biofilm setting, (ii diffusion facilitates and emphasizes this growth advantage, (iii the magnitude of the growth advantage can also depend on the initial inoculation of the substratum, (iv a new mass transfer boundary condition was derived that allows to a priori control the expect the expected average thickness of the biofilm in terms of the model parameters.

  18. Differential effects of prednisone and growth hormone on fuel metabolism and insulin antagonism in humans

    Energy Technology Data Exchange (ETDEWEB)

    Horber, F.F.; Marsh, H.M.; Haymond, M.W. (Mayo Clinic, Rochester, MN (USA))

    1991-01-01

    Human growth hormone (hGH) and prednisone cause insulin resistance and glucose intolerance. However, it is unknown whether hGH and prednisone antagonize insulin action on protein, fat, and carbohydrate metabolism by a common or independent mechanism. Therefore, protein, fat, and carbohydrate metabolism was assessed simultaneously in four groups of eight subjects each after 7 days of placebo, recombinant DNA hGH (rhGH; 0.1 mg.kg-1.day-1), prednisone (0.8 mg.kg-1.day-1), or rhGH and prednisone administration after an 18-h fast and during gut infusion of glucose and amino acids (fed state). Fasting plasma glucose concentrations were similar during placebo and rhGH but elevated (P less than 0.001) during combined treatment, whereas plasma insulin concentrations were higher (237 +/- 57 pmol/ml, P less than 0.001) during combined than during placebo, rhGH, or prednisone treatment (34, 52, and 91 pM, respectively). In the fed state, plasma glucose concentrations were elevated only during combined treatment (11.3 +/- 2.1 mM, P less than 0.001). Plasma insulin concentrations were elevated during therapy with prednisone alone and rhGH alone (667 +/- 72 and 564 +/- 65 pmol/ml, respectively, P less than 0.001) compared with placebo (226 +/- 44 pmol/ml) but lower than with the combined rhGH and prednisone treatment (1249 +/- 54 pmol/ml, P less than 0.01). Protein oxidation {sup 14}C leucine increased (P less than 0.001) with prednisone therapy, decreased (P less than 0.001) with rhGH treatment, and was normal during the combined treatment.

  19. Reversal of acute experimental cerebral vasospasm by calcium antagonism with verapamil.

    Science.gov (United States)

    Leblanc, R; Feindel, W; Yamamoto, L; Milton, J G; Frojmovic, M M

    1984-02-01

    Acute vasospasm of the transclivally exposed basilar artery of anesthetised cats was produced by the subarachnoid injection of platelet-rich plasma (PRP) treated with enough adenosine diphosphate (ADP) to induce platelet aggregation and secretion. Vasorelaxation was produced by the topical application of the calcium antagonist verapamil. Changes in the internal diameter of the basilar artery were determined by measuring the blood column diameter from photomicrographs taken sequentially, at 5 minute intervals, through the operating microscope. Changes in blood vessel diameter are expressed as a plus or minus percentage of the pretreatment diameter. Arterial blood pressure and blood gas values were kept in the physiological range for the cat. The subarachnoid injection of PRP-ADP produced severe constriction of the basilar artery (mean constriction at 5 minutes after injection: -40.7% +/- 2.8 SEM). Platelet-free plasma, ADP alone and Elliott's A solution had no spasmogenic effect when injected into the subarachnoid space. The topical application of the calcium channel blocker verapamil (0.1 mg per kg) 30 minutes after the injection of PRP-ADP, with the basilar artery still in spasm (mean constriction: -23% +/- 3.5 SEM), produced prompt and dramatic vasodilation (mean dilation at 5 minutes after application: +52.7% +/- 18.1 SEM). This spasmolytic effect persisted in a decremental fashion for the 60 minute period of observation, by which time the previously constricted vessel had returned to its normal size. These observations indicate that the platelet fraction of whole blood may be involved in the genesis of acute vasospasm following subarachnoid hemmorrhage and that this phenomenon can be readily reversed by calcium antagonism. PMID:6704793

  20. Differential effects of prednisone and growth hormone on fuel metabolism and insulin antagonism in humans

    International Nuclear Information System (INIS)

    Human growth hormone (hGH) and prednisone cause insulin resistance and glucose intolerance. However, it is unknown whether hGH and prednisone antagonize insulin action on protein, fat, and carbohydrate metabolism by a common or independent mechanism. Therefore, protein, fat, and carbohydrate metabolism was assessed simultaneously in four groups of eight subjects each after 7 days of placebo, recombinant DNA hGH (rhGH; 0.1 mg.kg-1.day-1), prednisone (0.8 mg.kg-1.day-1), or rhGH and prednisone administration after an 18-h fast and during gut infusion of glucose and amino acids (fed state). Fasting plasma glucose concentrations were similar during placebo and rhGH but elevated (P less than 0.001) during combined treatment, whereas plasma insulin concentrations were higher (237 +/- 57 pmol/ml, P less than 0.001) during combined than during placebo, rhGH, or prednisone treatment (34, 52, and 91 pM, respectively). In the fed state, plasma glucose concentrations were elevated only during combined treatment (11.3 +/- 2.1 mM, P less than 0.001). Plasma insulin concentrations were elevated during therapy with prednisone alone and rhGH alone (667 +/- 72 and 564 +/- 65 pmol/ml, respectively, P less than 0.001) compared with placebo (226 +/- 44 pmol/ml) but lower than with the combined rhGH and prednisone treatment (1249 +/- 54 pmol/ml, P less than 0.01). Protein oxidation 14C leucine increased (P less than 0.001) with prednisone therapy, decreased (P less than 0.001) with rhGH treatment, and was normal during the combined treatment

  1. Interleukin-6 gene knockout antagonizes high-fat-induced trabecular bone loss.

    Science.gov (United States)

    Wang, Chunyu; Tian, Li; Zhang, Kun; Chen, Yaxi; Chen, Xiang; Xie, Ying; Zhao, Qian; Yu, Xijie

    2016-10-01

    The purpose of the study was to determine the roles of interleukin-6 (IL6) in fat and bone communication. Male wild-type (WT) mice and IL6 knockout (IL6(-/-)) mice were fed with either regular diet (RD) or high-fat diet (HFD) for 12 weeks. Bone mass and bone microstructure were evaluated by micro-computed tomography. Gene expression related to lipid and bone metabolisms was assayed with real-time quantitative polymerase chain reaction. Bone marrow cells from both genotypes were induced to differentiate into osteoblasts or osteoclasts, and treated with palmitic acid (PA). HFD increased the body weight and fat pad weight, and impaired lipid metabolism in both WT and IL6(-/-) mice. The dysregulation of lipid metabolism was more serious in IL6(-/-) mice. Trabecular bone volume fraction, trabecular bone number and trabecular bone thickness were significantly downregulated in WT mice after HFD than those in the RD (P alkaline phosphatase (ALP) activity and higher mRNA levels of Runx2 and Colla1 than those in WT osteoblasts both in the control and PA treatment group (P < 0.05). IL6(-/-) mice showed significantly lower mRNA levels of PPARγ and leptin and higher mRNA levels of adiponectin in comparison with WT mice on HFD. In conclusion, these findings suggested that IL6 gene deficiency antagonized HFD-induced bone loss. IL6 might bridge lipid and bone metabolisms and could be a new potential therapeutic target for lipid metabolism disturbance-related bone loss. PMID:27493246

  2. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

    Science.gov (United States)

    Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

    2013-09-01

    NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis. PMID:23772801

  3. Exploring the structural basis for selenium/mercury antagonism in Allium fistulosum

    Energy Technology Data Exchange (ETDEWEB)

    McNear, Jr., David H.; Afton, Scott E.; Caruso, Joseph A. (UCIN); (Kentucky)

    2012-12-10

    While continuing efforts are devoted to studying the mutually protective effect of mercury and selenium in mammals, few studies have investigated the mercury-selenium antagonism in plants. In this study, we report the metabolic fate of mercury and selenium in Allium fistulosum (green onion) after supplementation with sodium selenite and mercuric chloride. Analysis of homogenized root extracts via capillary reversed phase chromatography coupled with inductively coupled plasma mass spectrometry (capRPLC-ICP-MS) suggests the formation of a mercury-selenium containing compound. Micro-focused synchrotron X-ray fluorescence mapping of freshly excised roots show Hg sequestered on the root surface and outlining individual root cells, while Se is more evenly distributed throughout the root. There are also discrete Hg-only, Se-only regions and an overall strong correlation between Hg and Se throughout the root. Analysis of the X-ray absorption near edge structure (XANES) spectra show a 'background' of methylselenocysteine within the root with discrete spots of SeO{sub 3}{sup 2-}, Se{sup 0} and solid HgSe on the root surface. Mercury outlining individual root cells is possibly binding to sulfhydryl groups or plasma membrane or cell wall proteins, and in some places reacting with reduced selenium in the rhizosphere to form a mercury(II) selenide species. Together with the formation of the root-bound mercury(II) selenide species, we also report on the formation of cinnabar (HgS) and Hg{sup 0} in the rhizosphere. The results presented herein shed light on the intricate chemical and biological processes occurring within the rhizosphere that influence Hg and Se bioavailability and will be instrumental in predicting the fate and assisting in the remediation of these metals in the environment and informing whether or not fruit and vegetable food selection from aerial plant compartments or roots from plants grown in Hg contaminated soils, are safe for consumption.

  4. Copper Induces Vasorelaxation and Antagonizes Noradrenaline -Induced Vasoconstriction in Rat Mesenteric Artery

    Directory of Open Access Journals (Sweden)

    Yu-Chun Wang

    2013-11-01

    Full Text Available Background/Aims: Copper is an essential trace element for normal cellular function and contributes to critical physiological or pathological processes. The aim of the study was to investigate the effects of copper on vascular tone of rat mesenteric artery and compare the effects of copper on noradrenaline (NA and high K+ induced vasoconstriction. Methods: The rat mesenteric arteries were isolated and the vessel tone was measured by using multi wire myograph system in vitro. Blood pressure of carotid artery in rabbits was measured by using physiological data acquisition and analysis system in vivo. Results: Copper dose-dependently blunted NA-induced vasoconstriction of rat mesenteric artery. Copper-induced vasorelaxation was inhibited when the vessels were pretreated with NG-nitro-L-arginine methyl ester (L-NAME. Copper did not blunt high K+-induced vasoconstriction. Copper preincubation inhibited NA-evoked vasoconstriction and the inhibition was not affected by the presence of L-NAME. Copper preincubation showed no effect on high K+-evoked vasoconstriction. Copper chelator diethyldithiocarbamate trihydrate (DTC antagonized the vasoactivity induced by copper in rat mesenteric artery. In vivo experiments showed that copper injection (iv significantly decreased blood pressure of rabbits and NA or DTC injection (iv did not rescue the copper-induced hypotension and animal death. Conclusion: Copper blunted NA but not high K+-induced vasoconstriction of rat mesenteric artery. The acute effect of copper on NA-induced vasoconstriction was depended on nitric oxide (NO, but the effect of copper pretreatment on NA-induced vasoconstriction was independed on NO, suggesting that copper affected NA-induced vasoconstriction by two distinct mechanisms.

  5. MafB antagonizes phenotypic alteration induced by GM-CSF in microglia

    Energy Technology Data Exchange (ETDEWEB)

    Koshida, Ryusuke, E-mail: rkoshida-myz@umin.ac.jp; Oishi, Hisashi, E-mail: hoishi@md.tsukuba.ac.jp; Hamada, Michito; Takahashi, Satoru

    2015-07-17

    Microglia are tissue-resident macrophages which are distributed throughout the central nervous system (CNS). Recent studies suggest that microglia are a unique myeloid population distinct from peripheral macrophages in terms of origin and gene expression signature. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine regulating myeloid development, has been shown to stimulate proliferation and alter phenotype of microglia in vitro. However, how its signaling is modulated in microglia is poorly characterized. MafB, a bZip transcriptional factor, is highly expressed in monocyte-macrophage lineage cells including microglia, although its role in microglia is largely unknown. We investigated the crosstalk between GM-CSF signaling and MafB by analyzing primary microglia. We found that Mafb-deficient microglia grew more rapidly than wild-type microglia in response to GM-CSF. Moreover, the expression of genes associated with microglial differentiation was more downregulated in Mafb-deficient microglia cultured with GM-CSF. Notably, such differences between the genotypes were not observed in the presence of M-CSF. In addition, we found that Mafb-deficient microglia cultured with GM-CSF barely extended their membrane protrusions, probably due to abnormal activation of RhoA, a key regulator of cytoskeletal remodeling. Altogether, our study reveals that MafB is a negative regulator of GM-CSF signaling in microglia. These findings could provide new insight into the modulation of cytokine signaling by transcription factors in microglia. - Highlights: • GM-CSF alters the phenotype of microglia in vitro more potently than M-CSF. • Transcription factor MafB antagonizes the effect of GM-CSF on microglia in vitro. • MafB deficiency leads to RhoA activation in microglia in response to GM-CSF. • We show for the first time the function of MafB in microglia.

  6. Silencing Huntington's chorea: Is RNA Interference a Potential Cure?

    Directory of Open Access Journals (Sweden)

    Gerlinde A. Metz

    2006-01-01

    Full Text Available In 1872, George Huntington described Huntington's disease as characterized by motor, cognitive and psychiatric impairments. Huntington's disease is a dominant and autosomal mutation on chromosome 4 featuring the insertion of numerous CAG repeats. CAG codes for the amino acid, glutmanine that forms part of the Huntingtin protein (htt. Excess glutamine attachments make htt prone to accumulate in neurons. Three genes can be considered when developing therapies for Huntington's disease. They include targeting the symptoms of the disease, the progression of the disease and the cause of the disease. By using RNA interference (RNAi, the cause of the disease can be targeted. RNAi is a method that could potentially silence the formation of abnormal htt. This paper will discuss how RNAi could potentially cure Huntington's disease, by describing the genetic and proteinomic basis of Huntington's disease, the function of RNAi in Huntington's disease and the problems of benefits of RNAi. Preliminary work using RNAi in transgenic mice has shown a decrease in the behavioural expression of the mutant Huntington gene. There are several limitations associated with using RNAi as a gene therapy. For example, the effects of RNAi are short lived. A transposition system such as Sleeping Beauty can be used to increase the integration of the gene, however, for patients who currently have Huntington's disease, RNAi may potentially be used in combination with drugs or other treatments to target both symptoms and the underlying cause of Huntington's disease. This combination could eventually alleviate many painful symptoms associated with Huntington's disease and could even stop the progressive neurodegeneration of Huntington's disease. This review concludes that a substantial amount of new research is still necessary before RNAi is directly applicable to human patients with Huntington's disease.

  7. Evidence for large complex networks of plant short silencing RNAs.

    Directory of Open Access Journals (Sweden)

    Daniel MacLean

    Full Text Available BACKGROUND: In plants and animals there are many classes of short RNAs that carry out a wide range of functions within the cell; short silencing RNAs (ssRNAs of 21-25 nucleotides in length are produced from double-stranded RNA precursors by the protein Dicer and guide nucleases and other proteins to their RNA targets through base pairing interactions. The consequence of this process is degradation of the targeted RNA, suppression of its translation or initiation of secondary ssRNA production. The secondary ssRNAs in turn could then initiate further layers of ssRNA production to form extensive cascades and networks of interacting RNA [1]. Previous empirical analysis in plants established the existence of small secondary ssRNA cascade [2], in which a single instance of this event occurred but it was not known whether there are other more extensive networks of secondary sRNA production. METHODOLOGY/PRINCIPAL FINDINGS: We generated a network by predicting targets of ssRNA populations obtained from high-throughput sequencing experiments. The topology of the network shows it to have power law connectivity distribution, to be dissortative, highly clustered and composed of multiple components. We also identify protein families, PPR and ULP1, that act as hubs within the network. Comparison of the repetition of genomic sub-sequences of ssRNA length between Arabidopsis and E.coli suggest that the network structure is made possible by the underlying repetitiveness in the genome sequence. CONCLUSIONS/SIGNIFICANCE: Together our results provide good evidence for the existence of a large, robust ssRNA interaction network with distinct regulatory function. Such a network could have a massive effect on the regulation of gene expression via mediation of transcript levels.

  8. Tumor Selective Silencing Using an RNAi-Conjugated Polymeric Nanopharmaceutical.

    Science.gov (United States)

    Svenson, Sonke; Case, Roy I; Cole, Roderick O; Hwang, Jungyeon; Kabir, Sujan R; Lazarus, Douglas; Lim Soo, Patrick; Ng, Pei-Sze; Peters, Christian; Shum, Pochi; Sweryda-Krawiec, Beata; Tripathi, Snehlata; van der Poll, Derek; Eliasof, Scott

    2016-03-01

    Small interfering RNA (siRNA) therapeutics have potential advantages over traditional small molecule drugs such as high specificity and the ability to inhibit otherwise "undruggable" targets. However, siRNAs have short plasma half-lives in vivo, can induce a cytokine response, and show poor cellular uptake. Formulating siRNA into nanoparticles offers two advantages: enhanced siRNA stability against nuclease degradation beyond what chemical modification alone can provide; and improved site-specific delivery that takes advantage of the enhanced permeability and retention (EPR) effect. Existing delivery systems generally suffer from poor delivery to tumors. Here we describe the formation and biological activity of polymeric nanopharmaceuticals (PNPs) based on biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) conjugated to siRNA via an intracellular cleavable disulfide linker (PLGA-siRNA). Additionally, these PNPs contain (1) PLGA conjugated to polyethylene glycol (PEG) for enhanced pharmacokinetics of the nanocarrier; (2) a cation for complexation of siRNA and charge compensation to avoid high negative zeta potential; and (3) neutral poly(vinyl alcohol) (PVA) to stabilize the PNPs and support the PEG shell to prevent particle aggregation and protein adsorption. The biological data demonstrate that these PNPs achieve prolonged circulation, tumor accumulation that is uniform throughout the tumor, and prolonged tumor-specific knockdown. PNPs employed in this study had no effect on body weight, blood cell count, serum chemistry, or cytokine response at doses >10 times the effective dose. PNPs, therefore, constitute a promising solution for achieving durable siRNA delivery and gene silencing in tumors. PMID:26835715

  9. Alpha fetoprotein antagonizes apoptosis induced by paclitaxel in hepatoma cells in vitro.

    Science.gov (United States)

    Zhu, Mingyue; Li, Wei; Lu, Yan; Dong, Xu; Chen, Yi; Lin, Bo; Xie, Xieju; Guo, Junli; Li, Mengsen

    2016-01-01

    Hepatocellular carcinoma (HCC) cell resistance to the effects of paclitaxel has not been adequately addressed. In this study, we found that paclitaxel significantly inhibited the viability of HLE, Bel 7402 and L-02 cells in a dose- and time-dependent manner. HLE cells and L-02 cells resisted the cytotoxicity of paclitaxel when transfected with pcDNA3.1-afp vectors. However, Bel 7402 cell sensitivity to paclitaxel was increased when transfected with alpha fetoprotein (AFP)-siRNA. Bel 7402 cell resistance to paclitaxel was associated with the expression of the "stemness" markers CD44 and CD133. Paclitaxel significantly inhibited growth and promoted apoptosis in HLE cells and L-02 cells by inducing fragmentation of caspase-3 and inhibiting the expression of Ras and Survivin, but pcDNA3.1-afp vectors prevented these effects. However, paclitaxel could not significantly promote the cleavage of caspase-3 or suppress the expression of Ras and Survivin in Bel 7402 cells. Silenced expression of AFP may be synergistic with paclitaxel to restrain proliferation and induce apoptosis, enhance cleavage of caspase-3, and suppress the expression of Ras and Survivin. Taken together, AFP may be an important molecule acting against paclitaxel-inhibited proliferation and induced apoptosis in HCC cells via repressing the activity of caspase-3 and stimulating the expression of Ras and Survivin. Targeted inhibition of AFP expression after treatment with paclitaxel is an available strategy for the therapy of patients with HCC. PMID:27255186

  10. BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2.

    Directory of Open Access Journals (Sweden)

    Qian Xiao

    Full Text Available An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1 was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2 as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.

  11. Development of a gene silencing DNA vector derived from a broad host range geminivirus

    Directory of Open Access Journals (Sweden)

    Hancock Leandria C

    2009-07-01

    Full Text Available Abstract Background Gene silencing is proving to be a powerful tool for genetic, developmental, and physiological analyses. The use of viral induced gene silencing (VIGS offers advantages to transgenic approaches as it can be potentially applied to non-model systems for which transgenic techniques are not readily available. However, many VIGS vectors are derived from Gemini viruses that have limited host ranges. We present a new, unipartite vector that is derived from a curtovirus that has a broad host range and will be amenable to use in many non-model systems. Results The construction of a gene silencing vector derived from the geminivirus Beet curly top virus (BCTV, named pWSRi, is reported. Two versions of the vector have been developed to allow application by biolistic techniques or by agro-infiltration. We demonstrate its ability to silence nuclear genes including ribulose bisphosphate carboxylase small subunit (rbcS, transketolase, the sulfur allele of magnesium chelatase (ChlI, and two homeotic transcription factors in spinach or tomato by generating gene-specific knock-down phenotypes. Onset of phenotypes occurred 3 to 12 weeks post-inoculation, depending on the target gene, in organs that developed after the application. The vector lacks movement genes and we found no evidence for significant spread from the site of inoculation. However, viral amplification in inoculated tissue was detected and is necessary for systemic silencing, suggesting that signals generated from active viral replicons are efficiently transported within the plant. Conclusion The unique properties of the pWSRi vector, the ability to silence genes in meristem tissue, the separation of virus and silencing phenotypes, and the broad natural host range of BCTV, suggest that it will have wide utility.

  12. Development of RNA Interference Trigger-Mediated Gene Silencing in Entamoeba invadens.

    Science.gov (United States)

    Suresh, Susmitha; Ehrenkaufer, Gretchen; Zhang, Hanbang; Singh, Upinder

    2016-04-01

    Entamoeba histolytica, a protozoan parasite, is an important human pathogen and a leading parasitic cause of death. The organism has two life cycle stages, trophozoites, which are responsible for tissue invasion, and cysts, which are involved in pathogen transmission. Entamoeba invadens is the model system to study Entamoeba developmental biology, as high-grade regulated encystation and excystation are readily achievable. However, the lack of gene-silencing tools in E. invadens has limited the molecular studies that can be performed. Using the endogenous RNA interference (RNAi) pathway in Entamoeba, we developed an RNAi-based trigger gene-silencing approach inE. invadens We demonstrate that a gene's coding region that has abundant antisense small RNAs (sRNAs) can trigger silencing of a gene that is fused to it. The trigger fusion leads to the generation of abundant antisense sRNAs that map to the target gene, with silencing occurring independently of trigger location at the 5' or 3' end of a gene. Gene silencing is stably maintained during development, including encystation and excystation. We have used this approach to successfully silence two E. invadens genes: a putative rhomboid protease gene and a SHAQKY family Myb gene. The Myb gene is upregulated during oxidative stress and development, and its downregulation led, as predicted, to decreased viability under oxidative stress and decreased cyst formation. Thus, the RNAi trigger silencing method can be used to successfully investigate the molecular functions of genes inE. invadens Dissection of the molecular basis of Entamoeba stage conversion is now possible, representing an important technical advance for the system. PMID:26787723

  13. Development of RNA Interference Trigger-Mediated Gene Silencing in Entamoeba invadens.

    Science.gov (United States)

    Suresh, Susmitha; Ehrenkaufer, Gretchen; Zhang, Hanbang; Singh, Upinder

    2016-04-01

    Entamoeba histolytica, a protozoan parasite, is an important human pathogen and a leading parasitic cause of death. The organism has two life cycle stages, trophozoites, which are responsible for tissue invasion, and cysts, which are involved in pathogen transmission. Entamoeba invadens is the model system to study Entamoeba developmental biology, as high-grade regulated encystation and excystation are readily achievable. However, the lack of gene-silencing tools in E. invadens has limited the molecular studies that can be performed. Using the endogenous RNA interference (RNAi) pathway in Entamoeba, we developed an RNAi-based trigger gene-silencing approach inE. invadens We demonstrate that a gene's coding region that has abundant antisense small RNAs (sRNAs) can trigger silencing of a gene that is fused to it. The trigger fusion leads to the generation of abundant antisense sRNAs that map to the target gene, with silencing occurring independently of trigger location at the 5' or 3' end of a gene. Gene silencing is stably maintained during development, including encystation and excystation. We have used this approach to successfully silence two E. invadens genes: a putative rhomboid protease gene and a SHAQKY family Myb gene. The Myb gene is upregulated during oxidative stress and development, and its downregulation led, as predicted, to decreased viability under oxidative stress and decreased cyst formation. Thus, the RNAi trigger silencing method can be used to successfully investigate the molecular functions of genes inE. invadens Dissection of the molecular basis of Entamoeba stage conversion is now possible, representing an important technical advance for the system.

  14. Silencing of CXCR2 and CXCR7 protects against esophageal cancer.

    Science.gov (United States)

    Wu, Kai; Cui, Lingling; Yang, Yang; Zhao, Jia; Zhu, Dengyan; Liu, Donglei; Zhang, Chunyang; Qi, Yu; Li, Xiangnan; Li, Weihao; Zhao, Song

    2016-01-01

    This study was aimed to investigate the functional roles of cytokine receptor (CXCR) CXCR2 and CXCR7 in esophageal cancer (EC). Specific small interfering RNAs (siRNA) against CXCR2 and CXCR7 were transfected into EC cell lines TE-1, EC9706, and EC109 cells. Expression of CXCR2 and CXCR7 was validated, along with cell viability, chemotaxis, apoptosis rate, and ERK1/2 pathways associated protein after transfection. Moreover, EC9706 cells treated with or without CXCR2/7 siRNA were injected into athymic nude mice. Tumor volumes were measured. Besides, immunohistochemical (IHC) staining was performed to investigate the expression of CXCR2/7 in adjacent normal tissues and tumor tissues from esophageal squamous cell carcinoma (ESCC) patients. Also, the associations between CXCR2/7 expression and clinicopathological features and progression were explored. The mRNA levels of CXCR2 and CXCR7 were significantly reduced after transfection. Silencing of CXCR2 and CXCR7 statistically decreased cell viability and chemotaxis, and increased apoptotic rate. Cells invasion was significantly reduced by silencing of CXCR2, however, no significance was found in silencing of CXCR7. The protein levels of pERK1/2 were significantly decreased by silencing of CXCR2 and CXCR7. Besides, silencing of CXCR2 and CXCR7 significantly reduced tumor growth in vivo, and associated with clinicopathological features and progression. Silencing of CXCR2 and CXCR7 protects against EC by inhibiting cell growth and chemotaxis, and inducing apoptosis though ERK1/2 pathways. Silencing of CXCR2 and CXCR7 has potentially therapeutic target for EC. PMID:27648130

  15. Specific tandem repeats are sufficient for paramutation-induced trans-generational silencing.

    Directory of Open Access Journals (Sweden)

    Christiane L Belele

    Full Text Available Paramutation is a well-studied epigenetic phenomenon in which trans communication between two different alleles leads to meiotically heritable transcriptional silencing of one of the alleles. Paramutation at the b1 locus involves RNA-mediated transcriptional silencing and requires specific tandem repeats that generate siRNAs. This study addressed three important questions: 1 are the tandem repeats sufficient for paramutation, 2 do they need to be in an allelic position to mediate paramutation, and 3 is there an association between the ability to mediate paramutation and repeat DNA methylation levels? Paramutation was achieved using multiple transgenes containing the b1 tandem repeats, including events with tandem repeats of only one half of the repeat unit (413 bp, demonstrating that these sequences are sufficient for paramutation and an allelic position is not required for the repeats to communicate. Furthermore, the transgenic tandem repeats increased the expression of a reporter gene in maize, demonstrating the repeats contain transcriptional regulatory sequences. Transgene-mediated paramutation required the mediator of paramutation1 gene, which is necessary for endogenous paramutation, suggesting endogenous and transgene-mediated paramutation both require an RNA-mediated transcriptional silencing pathway. While all tested repeat transgenes produced small interfering RNAs (siRNAs, not all transgenes induced paramutation suggesting that, as with endogenous alleles, siRNA production is not sufficient for paramutation. The repeat transgene-induced silencing was less efficiently transmitted than silencing induced by the repeats of endogenous b1 alleles, which is always 100% efficient. The variability in the strength of the repeat transgene-induced silencing enabled testing whether the extent of DNA methylation within the repeats correlated with differences in efficiency of paramutation. Transgene-induced paramutation does not require extensive

  16. Silencing of CXCR2 and CXCR7 protects against esophageal cancer

    Science.gov (United States)

    Wu, Kai; Cui, Lingling; Yang, Yang; Zhao, Jia; Zhu, Dengyan; Liu, Donglei; Zhang, Chunyang; Qi, Yu; Li, Xiangnan; Li, Weihao; Zhao, Song

    2016-01-01

    This study was aimed to investigate the functional roles of cytokine receptor (CXCR) CXCR2 and CXCR7 in esophageal cancer (EC). Specific small interfering RNAs (siRNA) against CXCR2 and CXCR7 were transfected into EC cell lines TE-1, EC9706, and EC109 cells. Expression of CXCR2 and CXCR7 was validated, along with cell viability, chemotaxis, apoptosis rate, and ERK1/2 pathways associated protein after transfection. Moreover, EC9706 cells treated with or without CXCR2/7 siRNA were injected into athymic nude mice. Tumor volumes were measured. Besides, immunohistochemical (IHC) staining was performed to investigate the expression of CXCR2/7 in adjacent normal tissues and tumor tissues from esophageal squamous cell carcinoma (ESCC) patients. Also, the associations between CXCR2/7 expression and clinicopathological features and progression were explored. The mRNA levels of CXCR2 and CXCR7 were significantly reduced after transfection. Silencing of CXCR2 and CXCR7 statistically decreased cell viability and chemotaxis, and increased apoptotic rate. Cells invasion was significantly reduced by silencing of CXCR2, however, no significance was found in silencing of CXCR7. The protein levels of pERK1/2 were significantly decreased by silencing of CXCR2 and CXCR7. Besides, silencing of CXCR2 and CXCR7 significantly reduced tumor growth in vivo, and associated with clinicopathological features and progression. Silencing of CXCR2 and CXCR7 protects against EC by inhibiting cell growth and chemotaxis, and inducing apoptosis though ERK1/2 pathways. Silencing of CXCR2 and CXCR7 has potentially therapeutic target for EC. PMID:27648130

  17. The rice yellow mottle virus P1 protein exhibits dual functions to suppress and activate gene silencing

    OpenAIRE

    Lacombe, Séverine; Bangratz, Martine; Vignols, Florence; Brugidou, Christophe

    2010-01-01

    In plants RNA silencing is a host defense mechanism against viral infection, in which double-strand RNA is processed into 21-24-nt short interfering RNA (siRNA). Silencing spreads from cell to cell and systemically through a sequence-specific signal to limit the propagation of the virus. To counteract this defense mechanism, viruses encode suppressors of silencing. The P1 protein encoded by the rice yellow mottle virus (RYMV) displays suppression activity with variable efficiency, according t...

  18. NK4 antagonizes Tbx1/10 to promote cardiac versus pharyngeal muscle fate in the ascidian second heart field.

    Directory of Open Access Journals (Sweden)

    Wei Wang

    2013-12-01

    Full Text Available The heart and head muscles share common developmental origins and genetic underpinnings in vertebrates, including humans. Parts of the heart and cranio-facial musculature derive from common mesodermal progenitors that express NKX2-5, ISL1, and TBX1. This ontogenetic kinship is dramatically reflected in the DiGeorge/Cardio-Velo-Facial syndrome (DGS/CVFS, where mutations of TBX1 cause malformations in the pharyngeal apparatus and cardiac outflow tract. Cardiac progenitors of the first heart field (FHF do not require TBX1 and segregate precociously from common progenitors of the second heart field (SHF and pharyngeal muscles. However, the cellular and molecular mechanisms that govern heart versus pharyngeal muscle specification within this lineage remain elusive. Here, we harness the simplicity of the ascidian larva to show that, following asymmetric cell division of common progenitors, NK4/NKX2-5 promotes GATAa/GATA4/5/6 expression and cardiac specification in the second heart precursors by antagonizing Tbx1/10-mediated inhibition of GATAa and activation of Collier/Olf/EBF (COE, the determinant of atrial siphon muscle (ASM specification. Our results uncover essential regulatory connections between the conserved cardio-pharyngeal factor Tbx1/10 and muscle determinant COE, as well as a mutual antagonism between NK4 and Tbx1/10 activities upstream of GATAa and COE. The latter cross-antagonism underlies a fundamental heart versus pharyngeal muscle fate choice that occurs in a conserved lineage of cardio-pharyngeal progenitors. We propose that this basic ontogenetic motif underlies cardiac and pharyngeal muscle development and evolution in chordates.

  19. Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus

    Energy Technology Data Exchange (ETDEWEB)

    Montrose, Kristopher; Krissansen, Geoffrey W., E-mail: gw.krissansen@auckland.ac.nz

    2014-10-31

    Highlights: • A novel proteolysis targeting chimeric molecule (PROTAC) to treat hepatitis B. • The PROTAC antagonizes and destroys the X-protein of the hepatitis B virus. • The PROTAC is a fusion of the X-protein oligomerization and instability domains. • The oligomerization domain is a dominant-negative inhibitor of X-protein function. • X-protein-targeting PROTACs have potential to prevent hepatocellular carcinoma. - Abstract: The X-protein of the hepatitis B virus (HBV) is essential for virus infection and contributes to the development of HBV-induced hepatocellular carcinoma (HCC), a disease which causes more than one million deaths each year. Here we describe the design of a novel PROTAC (proteolysis targeting chimeric molecule) capable of simultaneously inducing the degradation of the X-protein, and antagonizing its function. The PROTAC was constructed by fusing the N-terminal oligomerization and C-terminal instability domains of the X-protein to each other, and rendering them cell-permeable by the inclusion of a polyarginine cell-penetrating peptide (CPP). It was predicted that the oligomerization domain would bind the X-protein, and that the instability domain would cause the X-protein to be targeted for proteasomal degradation. Addition of the PROTAC to HepG2 liver cancer cells, engineered to express full-length and C-terminally truncated forms of the X-protein, resulted in the degradation of both forms of the X-protein. A cell-permeable stand-alone form of the oligomerization domain was taken up by HepG2 cells, and acted as a dominant-negative inhibitor, causing inhibition of X-protein-induced apoptosis. In summary, the PROTAC described here induces the degradation of the X-protein, and antagonizes its function, and warrants investigation in a preclinical study for its ability to prevent or treat HBV infection and/or the development of HCC.

  20. The VP3 factor from viruses of Birnaviridae family suppresses RNA silencing by binding both long and small RNA duplexes.

    Directory of Open Access Journals (Sweden)

    Adrian Valli

    Full Text Available RNA silencing is directly involved in antiviral defense in a wide variety of eukaryotic organisms, including plants, fungi, invertebrates, and presumably vertebrate animals. The study of RNA silencing-mediated antiviral defences in vertebrates is hampered by the overlap with other antiviral mechanisms; thus, heterologous systems are often used to study the interplay between RNA silencing and vertebrate-infecting viruses. In this report we show that the VP3 protein of the avian birnavirus Infectious bursal disease virus (IBDV displays, in addition to its capacity to bind long double-stranded RNA, the ability to interact with double-stranded small RNA molecules. We also demonstrate that IBDV VP3 prevents the silencing mediated degradation of a reporter mRNA, and that this silencing suppression activity depends on its RNA binding ability. Furthermore, we find that the anti-silencing activity of IBDV VP3 is shared with the homologous proteins expressed by both insect- and fish-infecting birnaviruses. Finally, we show that IBDV VP3 can functionally replace the well-characterized HCPro silencing suppressor of Plum pox virus, a potyvirus that is unable to infect plants in the absence of an active silencing suppressor. Altogether, our results support the idea that VP3 protects the viral genome from host sentinels, including those of the RNA silencing machinery.

  1. Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α

    Directory of Open Access Journals (Sweden)

    Ceran Ceyhan

    2012-10-01

    , but antagonistically on BT-474 cells. A representative anti-HER2 antibody inhibited Akt and ERK1/2 phosphorylation leading to cyclin D1 accumulation and growth arrest in SK-BR-3 cells, independently from TNF-α. Conclusions Novel antibodies against extracellular domain of HER2 may serve as potent anti-cancer bioactive molecules. Cell-dependent synergy and antagonism between anti-HER2 antibodies and TNF-α provide evidence for a complex interplay between HER2 and TNF-α signaling pathways. Such complexity may drastically affect the outcome of HER2-directed therapeutic interventions.

  2. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    Directory of Open Access Journals (Sweden)

    Christine eDugovic

    2014-02-01

    Full Text Available In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R and orexin-2 (OX2R receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM and REM sleep following oral dosing (10 and 30 mg/kg at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion. When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

  3. An interaction of ondansetron and dexamethasone antagonizing cisplatin-induced acute and delayed emesis in the ferret.

    OpenAIRE

    Rudd, J. A.; Naylor, R. J.

    1996-01-01

    1. Cisplatin, 5 mg kg-1, i.p., administered as a single treatment, induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of ondansetron and dexamethasone and their interaction over a three day period. 2. Ondansetron, 1 mg kg-1, i.p., administered three times per day in two experiments, antagonized significantly the retching and vomiting that occurred on days 1 and 2 by 60-76 and 73-84%. On the third da...

  4. Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism

    OpenAIRE

    Bourne, Yves; Radić, Zoran; Aráoz, Rómulo; Talley, Todd T.; Benoit, Evelyne; Servent, Denis; Taylor, Palmer; Molgó, Jordi; Marchot, Pascale

    2010-01-01

    Spirolide and gymnodimine macrocyclic imine phycotoxins belong to an emerging class of chemical agents associated with marine algal blooms and shellfish toxicity. Analysis of 13-desmethyl spirolide C and gymnodimine A by binding and voltage-clamp recordings on muscle-type α12βγδ and neuronal α3β2 and α4β2 nicotinic acetylcholine receptors reveals subnanomolar affinities, potent antagonism, and limited subtype selectivity. Their binding to acetylcholine-binding proteins (AChBP), as soluble rec...

  5. Detection of Fusarium spp. and Trichoderma spp. and antagonism of Trichoderma sp. in soybean under no-tillage

    OpenAIRE

    Paola Mendes Milanesi; Elena Blume; Marlove Fátima Brião Muniz; Lia Rejane Silveira Reiniger; Zaida Inês Antoniolli; Emanuele Junges; Manoeli Lupatini

    2013-01-01

    This study aimed i) to quantify the occurrence of Fusarium spp. and Trichoderma spp. in rhizospheric soil, with and without symptoms of Sudden Death Syndrome (SDS) in eight soybean genotypes; ii) morphologically identify isolates of Fusarium spp. from roots with SDS; iii) evaluate the antagonism between Trichoderma spp. and Fusarium spp. isolates from rhizospheric soil and roots from with and without SDS, respectively; and iv) characterize through the ITS1-5.8S-ITS2 region of rDNA the isolate...

  6. Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wörtwein, Gitta; Fink-Jensen, Anders;

    2013-01-01

    Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-administration and hyperlocomotion paradigms....... In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence...

  7. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    DEFF Research Database (Denmark)

    Uller, Lena; Mathiesen, Jesper Mosolff; Alenmyr, Lisa;

    2007-01-01

    BACKGROUND: Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells......, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist...... inflammation even to the extent that this mechanism can explain the efficacy of ramatroban Udgivelsesdato: february...

  8. SlmA Antagonism of FtsZ Assembly Employs a Two-pronged Mechanism like MinCD

    OpenAIRE

    Shishen Du; Joe Lutkenhaus

    2014-01-01

    Assembly of the Z-ring over unsegregated nucleoids is prevented by a process called nucleoid occlusion (NO), which in Escherichia coli is partially mediated by SlmA. SlmA is a Z ring antagonist that is spatially regulated and activated by binding to specific DNA sequences (SlmA binding sites, SBSs) more abundant in the origin proximal region of the chromosome. However, the mechanism by which SBS bound SlmA (activated form) antagonizes Z ring assembly is controversial. Here, we report the isol...

  9. Breaking an Epigenetic Chromatin Switch: Curious Features of Hysteresis in Saccharomyces cerevisiae Telomeric Silencing

    Science.gov (United States)

    Nagaraj, Vijayalakshmi H.; Mukhopadhyay, Swagatam; Dayarian, Adel; Sengupta, Anirvan M.

    2014-01-01

    In addition to gene network switches, local epigenetic modifications to DNA and histones play an important role in all-or-none cellular decision-making. Here, we study the dynamical design of a well-characterized epigenetic chromatin switch: the yeast SIR system, in order to understand the origin of the stability of epigenetic states. We study hysteresis in this system by perturbing it with a histone deacetylase inhibitor. We find that SIR silencing has many characteristics of a non-linear bistable system, as observed in conventional genetic switches, which are based on activities of a few promoters affecting each other through the abundance of their gene products. Quite remarkably, our experiments in yeast telomeric silencing show a very distinctive pattern when it comes to the transition from bistability to monostability. In particular, the loss of the stable silenced state, upon increasing the inhibitor concentration, does not seem to show the expected saddle node behavior, instead looking like a supercritical pitchfork bifurcation. In other words, the ‘off’ state merges with the ‘on’ state at a threshold concentration leading to a single state, as opposed to the two states remaining distinct up to the threshold and exhibiting a discontinuous jump from the ‘off’ to the ‘on’ state. We argue that this is an inevitable consequence of silenced and active regions coexisting with dynamic domain boundaries. The experimental observations in our study therefore have broad implications for the understanding of chromatin silencing in yeast and beyond. PMID:25536038

  10. Foxtail Mosaic Virus-Induced Gene Silencing in Monocot Plants1[OPEN

    Science.gov (United States)

    Liu, Na; Xie, Ke; Jia, Qi; Zhao, Jinping; Chen, Tianyuan; Li, Huangai; Wei, Xiang; Diao, Xianmin; Hong, Yiguo

    2016-01-01

    Virus-induced gene silencing (VIGS) is a powerful technique to study gene function in plants. However, very few VIGS vectors are available for monocot plants. Here we report that Foxtail mosaic virus (FoMV) can be engineered as an effective VIGS system to induce efficient silencing of endogenous genes in monocot plants including barley (Hordeum vulgare L.), wheat (Triticum aestivum) and foxtail millet (Setaria italica). This is evidenced by FoMV-based silencing of phytoene desaturase (PDS) and magnesium chelatase in barley, of PDS and Cloroplastos alterados1 in foxtail millet and wheat, and of an additional gene IspH in foxtail millet. Silencing of these genes resulted in photobleached or chlorosis phenotypes in barley, wheat, and foxtail millet. Furthermore, our FoMV-based gene silencing is the first VIGS system reported for foxtail millet, an important C4 model plant. It may provide an efficient toolbox for high-throughput functional genomics in economically important monocot crops. PMID:27225900

  11. Tomato Fruit Development and Ripening Are Altered by the Silencing of LeEIN2 Gene

    Institute of Scientific and Technical Information of China (English)

    Hong-Liang Zhu; Ben-Zhong Zhu; Yi Shao; Xiao-Guang Wang; Xi-Jin Lin; Yuan-Hong Xie; Ying-Cong Li; Hong-Yan Gao; Yun-Bo Luo

    2006-01-01

    Loss-of-function ethylene insensitive 2 (EIN2) mutations showed ethylene insensitivity in Arabidopsis,which indicated an essential role of EIN2 in ethylene signaling. However, the function of EIN2 in fruit ripening has not been investigated. To gain a better understanding of EIN2, the temporal regulation of LeEIN2 expression during tomato fruit development was analyzed. The expression of LeEIN2 was constant at different stages of fruit development, and was not regulated by ethylene. Moreover, LeEIN2-silenced tomato fruits were developed using a virus-induced gene silencing fruit system to study the role of LeEIN2 in tomato fruit ripening. Silenced fruits had a delay in fruit development and ripening, related to greatly descended expression of ethylene-related and ripening-related genes in comparison with those of control fruits. These results suggested LeEIN2 positively mediated ethylene signals during tomato development. In addition,there were fewer seeds and Iocules in the silenced fruit than those in the control fruit, like the phenotype of parthenocarpic tomato fruit. The content of auxin and the expression of auxin-regulated gene were declined in silenced fruit, which indicated that EIN2 might be important for crosstalk between ethylene and auxin hormones.

  12. Potential of Metal Fibre Felts as Passive Absorbers in Absorption Silencers

    Directory of Open Access Journals (Sweden)

    Björn Hinze

    2013-03-01

    Full Text Available The growing noise exposure of residents, due to a rising number of flights, causes significant impacts on physical health. Therefore it is necessary to reduce the noise emission of aircrafts. During take-off, the noise generated by the jet engines is dominating. One way to lower the noise emission of jet engines is to build an absorption silencer by using porous liners. Because of the high thermic and corrosive attacks as well as high fatigue loads, conventional absorbers cannot be used. A promising material is sintered metal fibre felts. This study investigates the suitability of metal fibre felts for the use as absorption material in silencers. The influences of pore morphology, absorption coefficient, determined with perpendicular sound incidence, as well as geometric parameters of the silencer to the damping are identified. To characterise the material, the parameters fibre diameter, porosity and thickness are determined using three-dimensional computer tomography images. The damping potential of absorption silencers is measured using an impedance tube, which was modified for transmission measurements. The essential parameter to describe the acoustic characteristics of porous materials is the flow resistivity. It depends on the size, shape and number of open pores in the material. Finally a connection between pore morphology, flow resistivity of the metal fibre felts and damping potential of the absorption silencer is given.

  13. A direct mixed-body boundary element method for packed silencers.

    Science.gov (United States)

    Wu, T W; Cheng, C Y R; Zhang, P

    2002-06-01

    Bulk-reacting sound absorbing materials are often used in packed silencers to reduce broadband noise. A bulk-reacting material is characterized by a complex mean density and a complex speed of sound. These two material properties can be measured by the two-cavity method or calculated by empirical formulas. Modeling the entire silencer domain with a bulk-reacting lining will involve two different acoustic media, air and the bulk-reacting material. Traditionally, the interior silencer domain is divided into different zones and a multi-domain boundary element method (BEM) may be applied to solve the problem. However, defining different zones and matching the elements along each interface is tedious, especially when the zones are intricately connected. In this paper, a direct mixed-body boundary element method is used to model a packed silencer without subdividing it into different zones. This is achieved by summing up all the integral equations in different zones and then adding the hypersingular integral equations at interfaces. Several test cases, including a packed expansion chamber with and without an absorbing center bullet, and a parallel baffle silencer, are studied. Numerical results for the prediction of transmission loss (TL) are compared to experimental data.

  14. Breaking an epigenetic chromatin switch: curious features of hysteresis in Saccharomyces cerevisiae telomeric silencing.

    Directory of Open Access Journals (Sweden)

    Vijayalakshmi H Nagaraj

    Full Text Available In addition to gene network switches, local epigenetic modifications to DNA and histones play an important role in all-or-none cellular decision-making. Here, we study the dynamical design of a well-characterized epigenetic chromatin switch: the yeast SIR system, in order to understand the origin of the stability of epigenetic states. We study hysteresis in this system by perturbing it with a histone deacetylase inhibitor. We find that SIR silencing has many characteristics of a non-linear bistable system, as observed in conventional genetic switches, which are based on activities of a few promoters affecting each other through the abundance of their gene products. Quite remarkably, our experiments in yeast telomeric silencing show a very distinctive pattern when it comes to the transition from bistability to monostability. In particular, the loss of the stable silenced state, upon increasing the inhibitor concentration, does not seem to show the expected saddle node behavior, instead looking like a supercritical pitchfork bifurcation. In other words, the 'off' state merges with the 'on' state at a threshold concentration leading to a single state, as opposed to the two states remaining distinct up to the threshold and exhibiting a discontinuous jump from the 'off' to the 'on' state. We argue that this is an inevitable consequence of silenced and active regions coexisting with dynamic domain boundaries. The experimental observations in our study therefore have broad implications for the understanding of chromatin silencing in yeast and beyond.

  15. The Malignant Phenotype of Breast Cancer Cells Is Reduced by COX-2 Silencing

    Directory of Open Access Journals (Sweden)

    Ioannis Stasinopoulos

    2008-11-01

    Full Text Available The cyclooxygenase (COX pathway is currently targeted for therapeutic intervention in different cancers. We have previously shown that silencing of COX-2 in the poorly differentiated metastatic breast cell line MDA-MB-231 by RNA interference markedly delayed tumor onset and inhibited metastasis. To understand the functional effects of COX-2 silencing underlying the inhibition of tumor growth and metastasis previously reported, we investigated changes in these cells for a number of cancer-associated phenotypes. Cyclooxygenase-2-silenced cells were less able to acidify tissue culture medium, a response that could partly be attributed to decreased lactate production or export detected by reduced lactate in the medium. Consistent with the significantly reduced transcript levels of hyaluronan synthase 2, an enzyme responsible for the total level of hyaluronan secreted by these cells, COX-2 silencing resulted in lower hyaluronan levels secreted in culture medium. Inhibition of human umbilical vein endothelial cell network association in a coculture assay was also observed in COX-2-silenced cells. These data highlight the functional role of COX-2 in pathways that mediate increased malignancy.

  16. Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3.

    Science.gov (United States)

    Shi, Z; Li, Z; Li, Z J; Cheng, K; Du, Y; Fu, H; Khuri, F R

    2015-05-01

    The cyclin-dependent kinase (CDK) inhibitor 1A, p21/Cip1, is a vital cell cycle regulator, dysregulation of which has been associated with a large number of human malignancies. One critical mechanism that controls p21 function is through its degradation, which allows the activation of its associated cell cycle-promoting kinases, CDK2 and CDK4. Thus delineating how p21 is stabilized and degraded will enhance our understanding of cell growth control and offer a basis for potential therapeutic interventions. Here we report a novel regulatory mechanism that controls the dynamic status of p21 through its interaction with Cdk5 and Abl enzyme substrate 1 (Cables1). Cables1 has a proposed role as a tumor suppressor. We found that upregulation of Cables1 protein was correlated with increased half-life of p21 protein, which was attributed to Cables1/p21 complex formation and supported by their co-localization in the nucleus. Mechanistically, Cables1 interferes with the proteasome (Prosome, Macropain) subunit alpha type 3 (PSMA3) binding to p21 and protects p21 from PSMA3-mediated proteasomal degradation. Moreover, silencing of p21 partially reverses the ability of Cables1 to induce cell death and inhibit cell proliferation. In further support of a potential pathophysiological role of Cables1, the expression level of Cables1 is tightly associated with p21 in both cancer cell lines and human lung cancer patient tumor samples. Together, these results suggest Cables1 as a novel p21 regulator through maintaining p21 stability and support the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21. PMID:24975575

  17. Integrating small molecule signalling and H-NS antagonism in Vibrio cholerae, a bacterium with two chromosomes.

    Science.gov (United States)

    Dorman, Charles J

    2015-08-01

    H-NS is a well-established silencer of virulence gene transcription in the human pathogen Vibrio cholerae. Biofilm formation aids V. cholerae in colonizing both its host and its external environments, and H-NS silences biofilm gene expression. Cyclic-di-guanosine monophosphate acts through the DNA binding proteins VpsR and VpsT to overcome H-NS-mediated repression of biofilm genes, driving a transition between a planktonic and a colonial/biofilm lifestyle. The H-NS binding pattern has now been charted on both chromosomes in V. cholerae, but whether or not this abundant DNA-binding-and-bridging protein plays any roles in nucleoid organization in this bacterium remains an open question.

  18. Silence acts as politeness strategy in the classroom——A case study of Chinese teacher students in intercultural MA classroom

    Institute of Scientific and Technical Information of China (English)

    Zhong Yanghui

    2010-01-01

    @@ Introduction With the development of paralinguistics, nonverbal interactions have drawn more and more attention (Larry et.al 2000) and silence is considered as the nonverbal interaction strategy in communication activities. Linguists have explored silence from different perspectives. According to Saville and Tannen, silence is used to perform positive, negative and off-record politeness strate-gies(Saville, 1985; Tannen, 1985). Moreover, Kurzon identifies intentional and unintentional silence, referring the former as silence used intentionally as a strategy while the later is silence caused due to extreme anxiety, embarrass-ment or panic(Kurzon, 1998).

  19. Something Blossoms in Between: Silence-Phenomena as a Bordering Notions in Psychology.

    Science.gov (United States)

    Lehmann Oliveros, Olga V

    2016-03-01

    Mysterious yet unavoidable, silence-phenomena appear to us in inherent ambiguity. In its plurality of meanings, phenomena related to silence are often perceived as overwhelming because they transcend the communicative capacity of language making it a challenge for cultural psychology to understand its involvement in our processes of making sense of experience and existence. Human growth and development involve processes where presence, void and content, voice, sound and noise, motion, transition and stillness, have dialectic interactions. In this article I discuss silence-phenomena as a bordering notion in terms of its discursive quality, the silent quality of speech, and the awareness of the ineffable. In addition, I highlight the possible implications of such notion in the understanding of affect from the perspective of Semiotic Cultural Psychology. I also emphasize the importance of considering psychological borders as multi-dimensional, taking the phenomenological experience of temporality as an illustration, which is also related to high emotional involvement of attention. PMID:26232279

  20. RNAi-induced silencing of embryonic tryptophan oxygenase in the Pyralid moth, Plodia interpunctella

    Directory of Open Access Journals (Sweden)

    Jeffrey A. Fabrick

    2004-05-01

    Full Text Available Gene silencing through the introduction of double-stranded RNA (RNA interference, RNAi provides a powerful tool for the elucidation of gene function in many systems, including those where genomics and proteomics are incomplete. The use of RNAi technology for gene silencing in Lepidoptera has lacked significant attention compared to other systems. To demonstrate that RNAi can be utilized in the lepidopteran, Plodia interpunctella, we cloned a cDNA for tryptophan oxygenase, and showed that silencing of tryptophan oxygenase through RNAi during embryonic development resulted in loss of eye-color pigmentation. The complete amino acid sequence of Plodia tryptophan oxygenase can be accessed through NCBI Protein Database under NCBI Accession # AY427951.

  1. Gene silencing by RNA interference in the house dust mite, Dermatophagoides pteronyssinus.

    Science.gov (United States)

    Marr, Edward J; Sargison, Neil D; Nisbet, Alasdair J; Burgess, Stewart T G

    2015-12-01

    This is the first report of gene silencing by RNA interference (RNAi) in the European house dust mite, Dermatophagoides pteronyssinus, Trouessart, 1897. Using a non-invasive immersion method first developed for the honey bee mite, Varroa destructor, a significant reduction in the expression of D. pteronyssinus glutathione-S-transferase mu-class 1 enzyme (DpGST-mu1) was achieved following overnight immersion in double stranded RNA encoding DpGST-mu1. Although no detrimental phenotypic changes were observed following silencing, this technique can now be used to address fundamental physiological questions and assess the potential therapeutic benefit in silencing D. pteronyssinus target genes in selected domestic situations of high human-mite interface. PMID:26212476

  2. A mode matching method for modeling dissipative silencers lined with poroelastic materials and containing mean flow.

    Science.gov (United States)

    Nennig, Benoit; Perrey-Debain, Emmanuel; Ben Tahar, Mabrouk

    2010-12-01

    A mode matching method for predicting the transmission loss of a cylindrical shaped dissipative silencer partially filled with a poroelastic foam is developed. The model takes into account the solid phase elasticity of the sound-absorbing material, the mounting conditions of the foam, and the presence of a uniform mean flow in the central airway. The novelty of the proposed approach lies in the fact that guided modes of the silencer have a composite nature containing both compressional and shear waves as opposed to classical mode matching methods in which only acoustic pressure waves are present. Results presented demonstrate good agreement with finite element calculations provided a sufficient number of modes are retained. In practice, it is found that the time for computing the transmission loss over a large frequency range takes a few minutes on a personal computer. This makes the present method a reliable tool for tackling dissipative silencers lined with poroelastic materials.

  3. RNAi mediated gene silencing against betasatellite associated with Croton yellow vein mosaic begomovirus.

    Science.gov (United States)

    Sahu, Anurag Kumar; Marwal, Avinash; Nehra, Chitra; Choudhary, Devendra Kumar; Sharma, Pradeep; Gaur, Rajarshi Kumar

    2014-11-01

    Plant viruses encode suppressors of posttranscriptional gene silencing, an adaptive antiviral defense responses that confines virus infection. Previously, we identified single-stranded DNA satellite (also known as DNA-β) of ~1,350 nucleotides in length associated with Croton yellow vein mosaic begomovirus (CYVMV) in croton plants. The expression of genes from DNA-β requires the begomovirus for packaged, replication, insect transmission and movement in plants. The present study demonstrates the effect of the βC1 gene on the silencing pathway as analysed by using both transgenic systems and transient Agrobacterium tumefaciens based delivery. Plants that carry an intron-hairpin construct covering the βC1 gene accumulated cognate small-interfering RNAs and remained symptom-free after exposure to CYVMV and its satellite. These results suggest that βC1 interferes with silencing mechanism.

  4. Something Blossoms in Between: Silence-Phenomena as a Bordering Notions in Psychology.

    Science.gov (United States)

    Lehmann Oliveros, Olga V

    2016-03-01

    Mysterious yet unavoidable, silence-phenomena appear to us in inherent ambiguity. In its plurality of meanings, phenomena related to silence are often perceived as overwhelming because they transcend the communicative capacity of language making it a challenge for cultural psychology to understand its involvement in our processes of making sense of experience and existence. Human growth and development involve processes where presence, void and content, voice, sound and noise, motion, transition and stillness, have dialectic interactions. In this article I discuss silence-phenomena as a bordering notion in terms of its discursive quality, the silent quality of speech, and the awareness of the ineffable. In addition, I highlight the possible implications of such notion in the understanding of affect from the perspective of Semiotic Cultural Psychology. I also emphasize the importance of considering psychological borders as multi-dimensional, taking the phenomenological experience of temporality as an illustration, which is also related to high emotional involvement of attention.

  5. Different uses of silence explained by observing high-context cultures and low-context cultures

    Institute of Scientific and Technical Information of China (English)

    张奕雯

    2011-01-01

    Silence, as a form of nonverbal communication, may be interpreted in various ways depending upon the culture. The pur- pose of this study is to explain misunderstanding concerned with the uses of silence in conversations situated in different cuhural backgrounds, and then give possible methods to avoid it. The explanation is mainly based on the two categories related to the context posed by Edward Hall: high-context culture & low-context culture. In this part, the study also contrasts distinct verbal styles in America & Japan, in addition, it analyses different attitudes towards silence from 3 aspects: traditional value, religion and power distance. At end, the study is concluded with 4 solutions that try to solve the problem.

  6. Gene transfer engineering for astrocyte-specific silencing in the CNS.

    Science.gov (United States)

    Merienne, N; Delzor, A; Viret, A; Dufour, N; Rey, M; Hantraye, P; Déglon, N

    2015-10-01

    Cell-type-specific gene silencing is critical to understand cell functions in normal and pathological conditions, in particular in the brain where strong cellular heterogeneity exists. Molecular engineering of lentiviral vectors has been widely used to express genes of interest specifically in neurons or astrocytes. However, we show that these strategies are not suitable for astrocyte-specific gene silencing due to the processing of small hairpin RNA (shRNA) in a cell. Here we develop an indirect method based on a tetracycline-regulated system to fully restrict shRNA expression to astrocytes. The combination of Mokola-G envelope pseudotyping, glutamine synthetase promoter and two distinct microRNA target sequences provides a powerful tool for efficient and cell-type-specific gene silencing in the central nervous system. We anticipate our vector will be a potent and versatile system to improve the targeting of cell populations for fundamental as well as therapeutic applications. PMID:26109254

  7. RNA interference silencing of CHS greatly alters the growth pattern of apple (Malus x domestica).

    Science.gov (United States)

    Dare, Andrew P; Hellens, Roger P

    2013-08-01

    Plants produce a vast array of phenolic compounds which are essential for their survival on land. One major class of polyphenols are the flavonoids and their formation is dependent on the enzyme chalcone synthase (CHS). In a recent study we silenced the CHS genes of apple (Malus × domestica Borkh.) and observed a loss of pigmentation in the fruit skin, flowers and stems. More surprisingly, highly silenced lines were significantly reduced in size, with small leaves and shortened internode lengths. Chemical analysis also revealed that the transgenic shoots contained greatly reduced concentrations of flavonoids which are known to modulate auxin flow. An auxin transport study verified this, with an increased auxin transport in the CHS-silenced lines. Overall, these findings suggest that auxin transport in apple has adapted to take place in the presence of high endogenous concentrations of flavonoids. Removal of these compounds therefore results in abnormal auxin movement and a highly disrupted growth pattern.

  8. Generation of tobacco lines with widely different reduction in nicotine levels via RNA silencing approaches

    Indian Academy of Sciences (India)

    Peng Wang; Zhifeng Liang; Jia Zeng Wenchao; Wenchao Li; Xiaofen Sun; Zhiqi Miao; Kexuan Tang

    2008-06-01

    Issues related to the nicotine content of tobacco have been public concerns. Several reports have described decreasing nicotine levels by silencing the putrescine N-methyltransferase (PMT) genes, but the reported variations of nicotine levels among transgenic lines are relatively low in general. Here we describe the generation in tobacco (Nicotiana tabacum) lines with widely different, reduced nicotine levels using three kinds of RNA-silencing approaches. The relative efficacies of suppression were compared among the three approaches regarding the aspect of nicotine level in tobacco leaves. By suppressing expression of the PMT genes, over 200 transgenic lines were obtained with nicotine levels reduced by 9.1–96.7%. RNA interference (RNAi) was the most efficient method of reducing the levels of nicotine, whereas cosuppression and antisense methods were less effective. This report gives clues to the efficient generation of plants with a variety of metabolite levels, and the results demonstrate the relative efficiencies of various RNA-silencing methods.

  9. MAGNUM OPUS: CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS BIOLOGY AND PROKARYOTIC GENE SILENCING

    Directory of Open Access Journals (Sweden)

    Prem Saran Tirumalai

    2013-01-01

    Full Text Available Gene Silencing was a technology that was established in eukaryotic system a decade ago and is being used as a research tool widely. However, prokaryotic gene silencing was not workable, till recently a team of researchers from the University of Georgia have proved it possible. Where they have shown that short motif sequences determines the targets of the prokaryotic Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR defence system is regulated by RNA guided Cas protein complex. Thus role of CRISPR system in microbial defense against foreign genetic material (Plasmid or Phages is an important milestone in the field of microbial molecular biology/biotechnology. These findings will make it easier to understand the significance of a gene, metabolically or physiologically. The revelation by this novel finding by core group of researcher is indeed, Mangum opus. This article is a commentary, to bring to light, prokaryotic gene silencing as one of the latest advances in prokaryotic science.

  10. Gene silencing and Polycomb group proteins: an overview of their structure, mechanisms and phylogenetics.

    Science.gov (United States)

    Golbabapour, Shahram; Majid, Nazia Abdul; Hassandarvish, Pouya; Hajrezaie, Maryam; Abdulla, Mahmood Ameen; Hadi, A Hamid A

    2013-06-01

    DNA methylation, histone modifications, and chromatin configuration are crucially important in the regulation of gene expression. Among these epigenetic mechanisms, silencing the expression of certain genes depending on developmental stage and tissue specificity is a key repressive system in genome programming. Polycomb (Pc) proteins play roles in gene silencing through different mechanisms. These proteins act in complexes and govern the histone methylation profiles of a large number of genes that regulate various cellular pathways. This review focuses on two main Pc complexes, Pc repressive complexes 1 and 2, and their phylogenetic relationship, structures, and function. The dynamic roles of these complexes in silencing will be discussed herein, with a focus on the recruitment of Pc complexes to target genes and the key factors involved in their recruitment. PMID:23692361

  11. H Ferritin Gene Silencing in a Human Metastatic Melanoma Cell Line: A Proteomic Analysis

    DEFF Research Database (Denmark)

    Di Sanzo, Maddalena; Gaspari, Marco; Misaggi, Roberta;

    2011-01-01

    Ferritin, the major intracellular iron-storage protein, is made of 24 subunits of two types, H and L. Besides regulating intracellular iron homeostasis, it has been found that ferritin, in particular the H subunit (FHC), is involved in different biological events such as cell differentiation...... in metabolic pathways related to tumor progression and metastasis. In vitro assays confirmed that the FHC-silenced MM07(m) cells are characterized by a decreased growth activity, a reduced invasiveness, and a reduced cell adhesion capability. Moreover, nude mice (CD1 nu/nu), subcutaneously injected with FHC......-silenced MM07(m) cells, showed a remarkable 4-fold reduction of their tumor growth capacity compared to those who received the FHC-unsilenced MM07(m) counterpart. In conclusion, these data indicate that gene silencing technology, coupled to proteomic analysis, is a powerful tool for a better understanding...

  12. Comparative analysis of RNA silencing suppression activities between viral suppressors and an endogenous plant RNA-dependent RNA polymerase.

    Science.gov (United States)

    Yoon, Ju-Yeon; Han, Kyoung-Sik; Park, Han-Yong; Choi, Seung-Kook

    2012-06-01

    RNA silencing is an evolutionarily conserved system that functions as an antiviral mechanism in eukaryotes, including higher plants. To counteract this, several plant viruses express silencing suppressors that inhibit RNA silencing in host plants. Here, we show that both 2b protein from peanut stunt virus (PSV) and a hairpin construct (designated hp-RDR6) that silences endogenous RNA-dependent RNA polymerase 6 (RDR6) strongly suppress RNA silencing. The Agrobacterium infiltration system was used to demonstrate that both PSV 2b and hp-RDR6 suppressed local RNA silencing as strongly as helper component (HC-Pro) from potato virus Y (PVY) and P19 from tomato bush stunt virus (TBSV). The 2b protein from PSV eliminated the small-interfering RNAs (siRNAs) associated with RNA silencing and prevented systemic silencing, similar to 2b protein from cucumber mosaic virus (CMV). On the other hand, hp-RDR6 suppressed RNA silencing by inhibiting the generation of secondary siRNAs. The small coat protein (SCP) of squash mosaic virus (SqMV) also displayed weak suppression activity of RNA silencing. Agrobacterium-mediated gene transfer was used to investigate whether viral silencing suppressors or hp-RDR6 enhanced accumulations of green fluorescence protein (GFP) and β-glucuronidase (GUS) as markers of expression in leaf tissues of Nicotina benthamiana. Expression of both GFP and GUS was significantly enhanced in the presence of PSV 2b or CMV 2b, compared to no suppression or the weak SqMV SCP suppressor. Co-expression with hp-RDR6 also significantly increased the expression of GFP and GUS to levels similar to those induced by PVY HC-Pro and TBSV P19.

  13. Displacement of Pathogens by an Engineered Bacterium Is a Multifactorial Process That Depends on Attachment Competition and Interspecific Antagonism.

    Science.gov (United States)

    Al-Saedi, Fitua; Stones, Daniel Henry; Vaz, Diana Pereira; Krachler, Anne Marie

    2016-06-01

    Pathogen attachment to host cells is a key process during infection, and inhibition of pathogen adhesion is a promising approach to the prevention of infectious disease. We have previously shown that multivalent adhesion molecules (MAMs) are abundant in both pathogenic and commensal bacterial species, mediate early attachment to host cells, and can contribute to virulence. Here, we investigated the efficacy of an engineered bacterium expressing a commensal MAM on its surface in preventing pathogen attachment and pathogen-mediated cytotoxicity in a tissue culture infection model. We were able to dissect the individual contributions of adhesion and interspecific antagonism on the overall outcome of infection for a range of different pathogens by comparison with the results obtained with a fully synthetic adhesion inhibitor. We found that the potential of the engineered bacterium to outcompete the pathogen is not always solely dependent on its ability to hinder host attachment but, depending on the pathogenic species, may also include elements of interspecific antagonism, such as competition for nutrients and its ability to cause a loss of fitness due to production of antimicrobial factors. PMID:27001540

  14. Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism.

    Science.gov (United States)

    Huang, Huang; Si, Pei; Wang, Lei; Xu, Yong; Xu, Xin; Zhu, Jin; Jiang, Hualiang; Li, Weihua; Chen, Lili; Li, Jian

    2015-07-01

    Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4'-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50 =12.2 ± 0.2 μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. PMID:25982493

  15. Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism.

    Science.gov (United States)

    Huang, Huang; Si, Pei; Wang, Lei; Xu, Yong; Xu, Xin; Zhu, Jin; Jiang, Hualiang; Li, Weihua; Chen, Lili; Li, Jian

    2015-07-01

    Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4'-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50 =12.2 ± 0.2 μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR.

  16. In vitro and in vivo antagonism of pathogenic turfgrass fungi by Streptomyces hygroscopicus strains YCED9 and WYE53.

    Science.gov (United States)

    Chamberlain, K; Crawford, D L

    1999-07-01

    Disease prevention is a current practice used to minimize fungal diseases of turfgrasses in lawns and golf greens. Prevention is accomplished through fungicide applications, and by periodic thatch removal. During the development of a microbial biodethatch product utilizing the lignocellulose-degrading Streptomyces hygroscopicus strains YCED9 and WYE53, we demonstrated using in vitro plate antagonism bioassays that both strains are antagonists of various turfgrass fungal pathogens. These activities were present when the cultures were growing on thatch, as demonstrated by antifungal antagonism bioassays with culture filtrates. Experiments conducted using a growth chamber demonstrated that a bio-dethatch formulation containing spores of strains YCED9 and WYE53 in a zeolite carrier, provided protection for Kentucky bluegrass seedlings against turfgrass pathogens, including Pythium ultimum, Fusarium oxysporum, Rhizoctonia solani, Sclerotinia homeocarpa, Gaeumannomyces graminis and Microdochium nivale. Results showed that by integrating the use of the S. hygroscopicus YCED9/WYE53 bio-dethatch formulation into routine turf management practices, it should be possible to both minimize thatch build-up while also controlling fungal turfgrass diseases by way of the antifungal biocontrol activity of these strains. This in turn would help control fungal pathogens in turfgrass while minimizing the need for routine chemical fungicide applications. PMID:10455494

  17. Fungal Antagonism Assessment of Predatory Species and Producers Metabolites and Their Effectiveness on Haemonchus contortus Infective Larvae

    Directory of Open Access Journals (Sweden)

    Manoel Eduardo Silva

    2015-01-01

    Full Text Available The objective of this study was to assess antagonism of nematophagous fungi and species producers metabolites and their effectiveness on Haemonchus contortus infective larvae (L3. Assay A assesses the synergistic, additive, or antagonistic effect on the production of spores of fungal isolates of the species Duddingtonia flagrans, Clonostachys rosea, Trichoderma esau, and Arthrobotrys musiformis; Assay B evaluates in vitro the effect of intercropping of these isolates grown in 2% water-agar (2% WA on L3 of H. contortus. D. flagrans (Assay A produced 5.3 × 106 spores and associated with T. esau, A. musiformis, or C. rosea reduced its production by 60.37, 45.28, and 49.05%, respectively. T. esau produced 7.9 × 107 conidia and associated with D. flagrans, A. musiformis, or C. rosea reduced its production by 39.24, 82.27, and 96.96%, respectively. A. musiformis produced 7.3 × 109 spores and associated with D. flagrans, T. esau, or C. rosea reduced its production by 99.98, 99.99, and 99.98%, respectively. C. rosea produced 7.3 × 108 conidia and associated with D. flagrans, T. esau, or A. musiformis reduced its production by 95.20, 96.84, and 93.56%, respectively. These results show evidence of antagonism in the production of spores between predators fungi.

  18. Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins.

    Science.gov (United States)

    Meng, Xiangzhi; Krumm, Brian; Li, Yongchao; Deng, Junpeng; Xiang, Yan

    2015-12-01

    Human sterile alpha motif domain-containing 9 (SAMD9) protein is a host restriction factor for poxviruses, but it can be overcome by some poxvirus host-range proteins that share homology with vaccinia virus C7 protein. To understand the mechanism of action for this important family of host-range factors, we determined the crystal structures of C7 and myxoma virus M64, a C7 family member that is unable to antagonize SAMD9. Despite their different functions and only 23% sequence identity, the two proteins have very similar overall structures, displaying a previously unidentified fold comprised of a compact 12-stranded antiparallel β-sandwich wrapped in two short α helices. Extensive structure-guided mutagenesis of C7 identified three loops clustered on one edge of the β sandwich as critical for viral replication and binding with SAMD9. The loops are characterized with functionally important negatively charged, positively charged, and hydrophobic residues, respectively, together forming a unique "three-fingered molecular claw." The key residues of the claw are not conserved in two C7 family members that do not antagonize SAMD9 but are conserved in distantly related C7 family members from four poxvirus genera that infect diverse mammalian species. Indeed, we found that all in the latter group of proteins bind SAMD9. Taken together, our data indicate that diverse mammalian poxviruses use a conserved molecular claw in a C7-like protein to target SAMD9 and overcome host restriction.

  19. Doppel-induced cytotoxicity in human neuronal SH-SY5Y cells is antagonized by the prion protein

    Institute of Scientific and Technical Information of China (English)

    Ping Li; Kun Xu; Chan Tian; Jun Han; Xiaoping Dong; Chenfang Dong; Yanjun Lei; Bing Shan; Xinli Xiao; Huiying Jiang; Xin Wang; Chen Gao; Qi Shi

    2009-01-01

    Doppel(Dpl)is a prion(PrP)-like protein due to the structural and biochemical similarities;however,the natural functions of Dpl and PrP remain unclear.In this study,a 531-bp human PRND gene sequence encoding Dpl protein was amplified from human peripheral blood leucocytes.Full-length and various truncated human Dpi and PrP proteins were expressed and purified from Escherichia coll.Supplement of the full-length Dpl onto human neuroblastoma cell SH-SY5Y induced remarkable cytotoxicity,and the region responsible for its cytotoxicity was mapped at the middle segment of Dpl [amino acids(aa)81-122].Interestingly,Dpl-induced cytotoxicity was antagonized by the presence of fulllength wild-type PrP.Analysis on fragments of PrP mutants showed that the N-terminal fragment(aa 23-90)of PrP was responsible for the protective activity.A truncated PrP(PrPA32-121)with similar secondary structure as Dpl induced Dpl-like cytotoxicity on SHSY5Y cells.Furthermore,binding of copper ion could enhance the antagonizing effect of PrP on Dpl-induced cytotoxicity.Apoptosis assays revealed that cytotoxicity induced by Dpl occurred through an apoptotic mechanism.These results suggested that the function of Dpi is antagonistic to PrP rather than synergistic.

  20. From silencing the self to action: experiences of women living with HIV/AIDS.

    Science.gov (United States)

    DeMarco, R F; Miller, K H; Patsdaughter, C A; Chisholm, M; Grindel, C G

    1998-01-01

    Feminist literature has demonstrated that women often maintain behaviors that support silencing of their voices. The critical issue is whether the silencing experience is (a) a destructive process of burying feelings and needs, (b) a protective strategy to preserve personal and professional relationships which they value, (c) a coping mechanism to divorce themselves from an androcentric/ethnocentric health care culture, or all of these. The transition from silence to action may be a process of reacting to a threat to self (i.e., HIV/AIDS diagnosis) where gender normative behaviors become irrelevant and self-advocacy becomes paramount for survival. Alternatively, the transition may be a conscious process of gaining insight into past behaviors that have been learned and culturally supported and making purposeful changes. Data for this study were extracted for secondary analysis from data from a larger study on experiences and needs of persons living with HIV/AIDS. Data were obtained from transcripts from three focus groups (N = 14 women) and six individual interviews. Women ranged in age from 21 to 55; 9 were European American, 7 were African American, and 4 were Latina American. Data were content analyzed and organized using four categories proposed by Jack (1991): (a) externalized self-perception, (b) care as self-sacrifice, (c) silencing the self, and (d) the divided self. Data supported that women with HIV/AIDS reported all four categories of silencing behaviors, particularly early in the HIV trajectory. For some women, an HIV/AIDS diagnosis ignited them to speak for themselves and to shape their own lives based on feelings and needs. For others, peer or professional support or both was the catalyst for the transition from silence to action. Findings suggest interventions that would assist women in judging themselves by internal versus external standards, putting their own needs before the perceived needs of others, expressing themselves toward action rather than

  1. (Regendering Memories of the Kosovo Liberation army: The Silenced Guerrilla of Women

    Directory of Open Access Journals (Sweden)

    Virginia Stephens

    2014-03-01

    Full Text Available Across the world and throughout history, women have played an active part in combat (Enloe, 1989; and Enloe, 2000 and yet discourses of war tend to be male domi-nated. Is the forgotten warfare of women in combat due to the absence of social exchanges or a deliberate choice of silencing? This paper argues for the latter by investi-gating the silencing of female combatants using the ex-ample of the Kosovo Liberation Army (KLA, and their subsequent lack of visibility and input in Kosovo’s na-tion-building project [1]. Based on preliminary findings from an oral history project with female KLA combat-ants, this paper seeks to question why, after having oc-cupied such a key place in combat, women have not de-fended their history, their words, their experiences – their memories – of their time at the front. It then ex-plores the different forces behind the silencing of their roles as combatants and the types of narrative allowed in collective memory and remembering. Breaking the silence of women combatants encourages an engage-ment with various gender frameworks that are absent from nation building narratives, and an understanding of what women are cultural products of. This paper does not aim to find heroes or glorify the hegemonic war narratives of the KLA, but rather to draw particular attention to the role of women combatants in post-war nation-building projects, such as Kosovo, and the silenc-ing of that role. In doing so, such a project intends to reframe how we remember and write national histories, as well as helping to shed light on the cultural construc-tion of gendered identities in a post-war era.

  2. RNA-mediated gene silencing in the cereal fungal pathogen Cochliobolus sativus.

    Science.gov (United States)

    Leng, Yueqiang; Wu, Chengxiang; Liu, Zhaohui; Friesen, Timothy L; Rasmussen, Jack B; Zhong, Shaobin

    2011-04-01

    A high-throughput RNA-mediated gene silencing system was developed for Cochliobolus sativus (anamorph: Bipolaris sorokiniana), the causal agent of spot blotch, common root rot and black point in barley and wheat. The green fluorescent protein gene (GFP) and the proteinaceous host-selective toxin gene (ToxA) were first introduced into C. sativus via the polyethylene glycol (PEG)-mediated transformation method. Transformants with a high level of expression of GFP or ToxA were generated. A silencing vector (pSGate1) based on the Gateway cloning system was developed and used to construct RNA interference (RNAi) vectors. Silencing of GFP and ToxA in the transformants was demonstrated by transformation with the RNAi construct expressing hairpin RNA (hpRNA) of the target gene. The polyketide synthase gene (CsPKS1), involved in melanin biosynthesis pathways in C. sativus, was also targeted by transformation with the RNAi vector (pSGate1-CsPKS1) encoding hpRNA of the CsPKS1 gene. The transformants with pSGate1-CsPKS1 exhibited an albino phenotype or reduced melanization, suggesting effective silencing of the endogenous CsPKS1 in C. sativus. Sectors exhibiting the wild-type phenotype of the fungus appeared in some of the CsPKS1-silenced transformants after subcultures as a result of inactivation or deletions of the RNAi transgene. The gene silencing system established provides a useful tool for functional genomics studies in C. sativus and other filamentous fungi.

  3. Silencing of six hydrophobins in Cladosporium fulvum: complexities of simultaneously targeting multiple genes.

    Science.gov (United States)

    Lacroix, Hélène; Spanu, Pietro D

    2009-01-01

    In this study, we have constructed and expressed inverted repeat chimeras from the first exons of the six known hydrophobins of the fungus Cladosporium fulvum, the causal agent of tomato leaf mold. We used quantitative PCR to measure specifically the expression levels of the hydrophobins. The targeted genes are silenced to different degrees, but we also detected clear changes in the expression levels of nontargeted genes. This work highlights the difficulties that are likely to be encountered when attempting to silence more than one gene in a multigene family.

  4. Satellite RNAs interfere with the function of viral RNA silencing suppressors

    OpenAIRE

    Wanxia eShen; Phil Chi Khang Au; Bu-Jun eShi; Smith, Neil A.; Dennis, Elizabeth S.; Hui-Shan eGuo; Chang-Yong eZhou; Ming-Bo eWang

    2015-01-01

    Viral satellite RNAs (satRNAs) are small subviral RNAs and depend on the helper virus for replication and spread. satRNAs can attenuate helper virus-induced symptoms, the mechanism of which remains unclear. Here, we show that two virus-encoded suppressors of RNA silencing (VSRs), Cucumber mosaic virus (CMV) 2b and Tombusvirus P19, suppress hairpin RNA (hpRNA)-induced silencing of a β-glucuronidase (GUS) gene in Nicotiana benthamiana. This suppression can be overcome by CMV Y-satellite RNA (Y-...

  5. Development of a large reactive silencer to attenuate mid frequency broad band sound: a case study

    Energy Technology Data Exchange (ETDEWEB)

    Sacks, M. P.; Kane, J.

    1996-08-01

    Development of a large reactive silencer, modifying the pollution control system of a fluid catalytic cracking unit at an east coast oil refinery, was described. The modification was necessitated by complaints from nearby residents, and company determination that sound levels in the community could reach 75dBA to 80 dBA under frequent downwind conditions in an otherwise quiet residential area. Design, construction and testing of a scale model, static testing of the full size silencer prior to delivery and installation, and preliminary in situ results were reviewed and discussed. 1 ref., 5 figs.

  6. The Miranda Right to silence in criminal trial : an economic analysis

    OpenAIRE

    Lang, Günther

    2005-01-01

    This paper analyzes the strategic implications for criminal trial of the existence of the famous Miranda Right to Silence in U.S. law doctrine. The right confers to the defendant the privilege that, in the context of a signalling game, i. e. the trial, no adverse conclusions may be drawn from his exercise of the right. It is shown that Miranda reduces wrongful confessions and convictions, at the price, however, of setting free guilty defendants as well. The rate of silence is affected only wh...

  7. Learning to be silent: theological and philosophical reflections on silence and transcendence

    OpenAIRE

    Wardley, Kenneth Jason

    2010-01-01

    ‘Libère-moi de la trop longue parole.’ (Maurice Blanchot, Le pas au-delà, 1973) Michèle le Doeuff suggested that theology rests upon a prior silencing of philosophy; the work of Jean-Yves Lacoste is unconcerned with any strict distinction between the disciplines where theology is an unsystematic, fragmentary and, above all, ethical activity, reminiscent of Stoker’s account of Derrida and the fourth type of messianic transcendence. While suffering can reduce theology to silence thi...

  8. ANTAGONISM AGAINST VIBRIO CHOLERAE BY BACTERIAL DIFFUSIBLE COMPOUND IN THE FECAL MICROBIOTA OF RODENTS

    Directory of Open Access Journals (Sweden)

    Simone Helena da Silva

    1998-09-01

    Full Text Available In an ex vivo agar plate assay, we monitored the appearance of an inhibitory halo against Vibrio cholerae from the feces of Wistar and Fischer rats aged 10 to 42 days. The frequency of Wistar rats showing halo increased from 0% (10 days to a maximum of 80.0% (29 days and then decreased to 53.3% (42 days. A similar pattern was obtained with Fischer rats but with a lower intensity (maximum frequency of 50.0% by day 36. In a separate experiment, when Wistar rats were fed a low-protein diet for 7 days, the inhibitory halo decreased drastically. Three apparently different colony morphologies were isolated from the dominant fecal microbiota: a facultative anaerobe (FAN and two strict anaerobes (SAN. The ex vivo inhibitory test showed a halo around the feces of germfree mice monoassociated with the FAN bacterium or one of the SAN bacterium but not of the germfree ones. After oral challenge of all groups with V. cholerae, a permissive and a drastic barrier effects were observed in mice with FAN and SAN associated bacteria, respectively. The FAN and one SAN bacteria used in the in vivo challenges were identified as Escherichia coli and Streptococcus intermedius, respectively. The potent antagonism developed by the rat intestinal microbiota against V. cholerae seems to be due, in part, to diffusible compounds and this phenomenon depends apparently on age, strain and nutrition of the animals. These preliminary results also suggest that this effect was due to more than one bacterial component at any given moment.O aparecimento de halo de inibição contra o Vibrio cholerae a partir das fezes de ratos Wistar e Fischer nas idades de 10 a 42 dias foi observado usando um teste ex vivo em placa. A frequência de ratos Wistar apresentando halo aumentou de 0% (10 dias até um máximo de 80,0% (29 dias antes de decair para 53,3% (42 dias. Um perfil similar foi obtido com os ratos Fischer mas com valores inferiores (frequência máxima de 50,0% no dia 36. Num

  9. The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA silencing in plants

    NARCIS (Netherlands)

    Bucher, E.C.; Hemmes, J.C.; Haan, de P.; Goldbach, R.W.; Prins, M.W.

    2004-01-01

    RNA silencing comprises a set of sequence-specific RNA degradation pathways that occur in a wide range of eukaryotes, including animals, fungi and plants. A hallmark of RNA silencing is the presence of small interfering RNA molecules (siRNAs). The siRNAs are generated by cleavage of larger double-st

  10. Uudised : Rannap sai raha lõpuks kätte. No Big Silence esitleb uut heliplaati

    Index Scriptorium Estoniae

    2000-01-01

    Pärnus toimunud lühima öö laulukonkursil võitis peaauhinna R. Rannap. Ans. No-Big-Silence on soojendusbändiks 2. juulil Tallinna Lauluväljakul toimuval Iron Maideni kontserdil. Ans. No-Big-Silence esitleb oma uut heliplaati "successful, bitch and beautiful"

  11. Microarray analysis of LTR retrotransposon silencing identifies Hdac1 as a regulator of retrotransposon expression in mouse embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Judith Reichmann

    Full Text Available Retrotransposons are highly prevalent in mammalian genomes due to their ability to amplify in pluripotent cells or developing germ cells. Host mechanisms that silence retrotransposons in germ cells and pluripotent cells are important for limiting the accumulation of the repetitive elements in the genome during evolution. However, although silencing of selected individual retrotransposons can be relatively well-studied, many mammalian retrotransposons are seldom analysed and their silencing in germ cells, pluripotent cells or somatic cells remains poorly understood. Here we show, and experimentally verify, that cryptic repetitive element probes present in Illumina and Affymetrix gene expression microarray platforms can accurately and sensitively monitor repetitive element expression data. This computational approach to genome-wide retrotransposon expression has allowed us to identify the histone deacetylase Hdac1 as a component of the retrotransposon silencing machinery in mouse embryonic stem cells, and to determine the retrotransposon targets of Hdac1 in these cells. We also identify retrotransposons that are targets of other retrotransposon silencing mechanisms such as DNA methylation, Eset-mediated histone modification, and Ring1B/Eed-containing polycomb repressive complexes in mouse embryonic stem cells. Furthermore, our computational analysis of retrotransposon silencing suggests that multiple silencing mechanisms are independently targeted to retrotransposons in embryonic stem cells, that different genomic copies of the same retrotransposon can be differentially sensitive to these silencing mechanisms, and helps define retrotransposon sequence elements that are targeted by silencing machineries. Thus repeat annotation of gene expression microarray data suggests that a complex interplay between silencing mechanisms represses retrotransposon loci in germ cells and embryonic stem cells.

  12. NK1 receptor antagonism lowers occupancy requirement for antidepressant-like effects of SSRIs in the gerbil forced swim test.

    Science.gov (United States)

    Lelas, Snjezana; Li, Yu-Wen; Wallace-Boone, Tanya L; Taber, Matthew T; Newton, Amy E; Pieschl, Rick L; Davis, Carl D; Molski, Thaddeus F; Newberry, Kimberly S; Parker, Michael F; Gillman, Kevin W; Bronson, Joanne J; Macor, John E; Lodge, Nicholas J

    2013-10-01

    The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.

  13. ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis.

    Science.gov (United States)

    Das, Sudipta; Czarnek, Maria; Bzowska, Monika; Mężyk-Kopeć, Renata; Stalińska, Krystyna; Wyroba, Barbara; Sroka, Jolanta; Jucha, Jarosław; Deneka, Dawid; Stokłosa, Paulina; Ogonek, Justyna; Swartz, Melody A; Madeja, Zbigniew; Bereta, Joanna

    2012-01-01

    ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

  14. ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Sudipta Das

    Full Text Available ADAM17 (a disintegrin and metalloprotease 17 is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

  15. Performances of Student Activism: Sound, Silence, Gender, and Dis/ability

    Science.gov (United States)

    Pasque, Penny A.; Vargas, Juanita Gamez

    2014-01-01

    This chapter explores the various performances of activism by students through sound, silence, gender, and dis/ability and how these performances connect to social change efforts around issues such as human trafficking, homeless children, hunger, and children with varying abilities.

  16. Setting the Record Straight: The Selection, Subordination and Silencing of Maata Patene, Teacher

    Science.gov (United States)

    Stephenson, Maxine

    2009-01-01

    Maori women teachers in nineteenth-century New Zealand have been little acknowledged in educational histories, and indeed, in some instances their contributions have been explicitly nullified. Those who have taken leadership roles have been no more visible. This article examines the silencing and exclusion from educational history of a young Maori…

  17. BIOFILTRATION INCORPORATING GENE SILENCING TECHNOLOGY FOR THE PRODUCTION OF METHANOL FROM METHANE CONTAINING WASTE GASES

    Science.gov (United States)

    I expect the proposed and revised approach will work, as there are multiple examples of plasmid-based gene silencing systems in nature (HOK/SOK is a perfect example). The challenge will be in developing a strong plasmid for use in methanotrophs. Potential to ...

  18. Transient silencing of CHALCONE SYNTHASE during fruit ripening modifies tomato epidermal cells and cuticle properties.

    Science.gov (United States)

    España, Laura; Heredia-Guerrero, José A; Reina-Pinto, José J; Fernández-Muñoz, Rafael; Heredia, Antonio; Domínguez, Eva

    2014-11-01

    Tomato (Solanum lycopersicum) fruit ripening is accompanied by an increase in CHALCONE SYNTHASE (CHS) activity and flavonoid biosynthesis. Flavonoids accumulate in the cuticle, giving its characteristic orange color that contributes to the eventual red color of the ripe fruit. Using virus-induced gene silencing in fruits, we have down-regulated the expression of SlCHS during ripening and compared the cuticles derived from silenced and nonsilenced regions. Silenced regions showed a pink color due to the lack of flavonoids incorporated to the cuticle. This change in color was accompanied by several other changes in the cuticle and epidermis. The epidermal cells displayed a decreased tangential cell width; a decrease in the amount of cuticle and its main components, cutin and polysaccharides, was also observed. Flavonoids dramatically altered the cuticle biomechanical properties by stiffening the elastic and viscoelastic phase and by reducing the ability of the cuticle to deform. There seemed to be a negative relation between SlCHS expression and wax accumulation during ripening that could be related to the decreased cuticle permeability to water observed in the regions silencing SlCHS. A reduction in the overall number of ester linkages present in the cutin matrix was also dependent on the presence of flavonoids.

  19. DNA replication factor C1 mediates genomic stability and transcriptional gene silencing in Arabidopsis

    KAUST Repository

    Liu, Qian

    2010-07-01

    Genetic screening identified a suppressor of ros1-1, a mutant of REPRESSOR OF SILENCING1 (ROS1; encoding a DNA demethylation protein). The suppressor is a mutation in the gene encoding the largest subunit of replication factor C (RFC1). This mutation of RFC1 reactivates the unlinked 35S-NPTII transgene, which is silenced in ros1 and also increases expression of the pericentromeric Athila retrotransposons named transcriptional silent information in a DNA methylationindependent manner. rfc1 is more sensitive than the wild type to the DNA-damaging agent methylmethane sulphonate and to the DNA inter- and intra- cross-linking agent cisplatin. The rfc1 mutant constitutively expresses the G2/M-specific cyclin CycB1;1 and other DNA repair-related genes. Treatment with DNA-damaging agents mimics the rfc1 mutation in releasing the silenced 35S-NPTII, suggesting that spontaneously induced genomic instability caused by the rfc1 mutation might partially contribute to the released transcriptional gene silencing (TGS). The frequency of somatic homologous recombination is significantly increased in the rfc1 mutant. Interestingly, ros1 mutants show increased telomere length, but rfc1 mutants show decreased telomere length and reduced expression of telomerase. Our results suggest that RFC1 helps mediate genomic stability and TGS in Arabidopsis thaliana. © 2010 American Society of Plant Biologists.

  20. Barriers and silencers: a theoretical toolkit for control and containment of nucleosome-based epigenetic states.

    Science.gov (United States)

    Dodd, Ian B; Sneppen, Kim

    2011-12-01

    Positive feedback in nucleosome modification has been proposed to allow large chromatin regions to exist stably and heritably in distinct expression states. However, modeling has shown that such epigenetic bistability requires that modifying enzymes recruited by nucleosomes are active on distant nucleosomes, potentially allowing uncontrollable spreading of modification. By modeling the silencing of mating-type loci in Saccharomyces cerevisiae, we show that a modification reaction that combines a long-range component and a locally acting component can provide bistability and can be blocked by simple barriers that interrupt the nucleosome chain. We find that robust containment of the silenced region could be achieved by the presence of a number of weak simple barriers in the surrounding chromatin and a limited capacity of the positive feedback reaction. In addition, we show that the state of the silenced region can be regulated by silencer elements acting only on neighboring nucleosomes. Thus, a relatively simple set of nucleosome-modifying enzymes and recognition domains is all that is needed to make chromatin-based epigenetics useful and safe. PMID:22037584

  1. Aquaporin-4 gene silencing protects injured neurons after early cerebral infarction

    Directory of Open Access Journals (Sweden)

    Zhan-ping He

    2015-01-01

    Full Text Available Aquaporin-4 regulates water molecule channels and is important in tissue regulation and water transportation in the brain. Upregulation of aquaporin-4 expression is closely related to cellular edema after early cerebral infarction. Cellular edema and aquaporin-4 expression can be determined by measuring cerebral infarct area and apparent diffusion coefficient using diffusion-weighted imaging (DWI. We examined the effects of silencing aquaporin-4 on cerebral infarction. Rat models of cerebral infarction were established by occlusion of the right middle cerebral artery and siRNA-aquaporin-4 was immediately injected via the right basal ganglia. In control animals, the area of high signal intensity and relative apparent diffusion coefficient value on T2-weighted imaging (T2WI and DWI gradually increased within 0.5-6 hours after cerebral infarction. After aquaporin-4 gene silencing, the area of high signal intensity on T2WI and DWI reduced, relative apparent diffusion coefficient value was increased, and cellular edema was obviously alleviated. At 6 hours after cerebral infarction, the apparent diffusion coefficient value was similar between treatment and model groups, but angioedema was still obvious in the treatment group. These results indicate that aquaporin-4 gene silencing can effectively relieve cellular edema after early cerebral infarction; and when conducted accurately and on time, the diffusion coefficient value and the area of high signal intensity on T2WI and DWI can reflect therapeutic effects of aquaporin-4 gene silencing on cellular edema.

  2. Transgene-based anthocyanin hyper-pigmentation as a visual reporter of gene silencing in plants

    Science.gov (United States)

    “Co-suppression” associated loss of flower pigmentation in transgenic petunia plants was one of the first clear indicators of the natural process of RNA-associated gene silencing in plants. We have been exploring the use of genetically engineered anthocyanin over-production in vegetative tissues as...

  3. The NS3 protein of rice hoja blanca virus suppresses RNA silencing in mammalian cells

    NARCIS (Netherlands)

    Schnettler, E.; Hemmes, J.C.; Goldbach, R.W.; Prins, M.W.

    2008-01-01

    The NS3 protein of the tenuivirus rice hoja blanca virus (RHBV) has previously been shown to represent the viral RNA interference (RNAi) suppressor and is active in both plant and insect cells by binding short interfering RNAs (siRNAs) in vitro. Using a firefly luciferase-based silencing assay it is

  4. Get Real! Silence and Boasting in J. Oppenheimer's The Act of Killing

    DEFF Research Database (Denmark)

    Hyldgaard, Kirsten

    2016-01-01

    This chapter examines what can be learned from Joshua Oppenheimer’s The Act of Killing and The Look of Silence which document the mass killing of up to one million Indonesians in connection with the military coup in 1965. The opposition between fiction and reality is discussed on the foundation...

  5. Aquaporin-4 gene silencing protects injured neurons after early cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Zhan-ping He; Hong Lu

    2015-01-01

    Aquaporin-4 regulates water molecule channels and is important in tissue regulation and water transportation in the brain. Upregulation of aquaporin-4 expression is closely related to cel-lular edema after early cerebral infarction. Cellular edema and aquaporin-4 expression can be determined by measuring cerebral infarct area and apparent diffusion coefficient using diffu-sion-weighted imaging (DWI). We examined the effects of silencing aquaporin-4 on cerebral infarction. Rat models of cerebral infarction were established by occlusion of the right middle cerebral artery and siRNA-aquaporin-4 was immediately injectedvia the right basal ganglia. In control animals, the area of high signal intensity and relative apparent diffusion coefifcient value on T2-weighted imaging (T2WI) and DWI gradually increased within 0.5–6 hours after cerebral infarction. After aquaporin-4 gene silencing, the area of high signal intensity on T2WI and DWI reduced, relative apparent diffusion coefifcient value was increased, and cellular edema was ob-viously alleviated. At 6 hours after cerebral infarction, the apparent diffusion coefifcient value was similar between treatment and model groups, but angioedema was still obvious in the treat-ment group. These results indicate that aquaporin-4 gene silencing can effectively relieve cellular edema after early cerebral infarction; and when conducted accurately and on time, the diffusion coefifcient value and the area of high signal intensity on T2WI and DWI can relfect therapeutic effects of aquaporin-4 gene silencing on cellular edema.

  6. After Brown U.'s Report on Slavery, Silence (So Far)

    Science.gov (United States)

    Bartlett, Thomas

    2006-01-01

    This article, discusses Brown University's slavery report, a 106-page narrative examination of the early connections between Brown University and slavery, that has been greeted--so far--with silence. The report, done at the behest of Ruth J. Simmons, Brown's president and herself a descendant of slaves, is an unsparing look at a shameful side of…

  7. Socrates, Augustine, and Paul Gauguin on the Reciprocity between Speech and Silence in Education

    Science.gov (United States)

    Caranfa, Angelo

    2013-01-01

    While most educational practices today place an excessive amount of attention on discourse, this article attaches great importance to the reciprocity between speech and silence by drawing from the writings of Plato's Socrates, Augustine, and Paul Gauguin for whom this reciprocity is of the essence in learning. These three figures teach that…

  8. Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint.

    Science.gov (United States)

    Chen, Jing; Liu, Jian

    2016-09-01

    Chromosome segregation during mitosis hinges on proper assembly of the microtubule spindle that establishes bipolar attachment to each chromosome. Experiments demonstrate allometry of mitotic spindles and a universal scaling relationship between spindle size and cell size across metazoans, which indicates a conserved principle of spindle assembly at play during evolution. However, the nature of this principle is currently unknown. Researchers have focused on deriving the mechanistic underpinning of the size scaling from the mechanical aspects of the spindle assembly process. In this work we take a different standpoint and ask: What is the size scaling for? We address this question from the functional perspectives of spindle assembly checkpoint (SAC). SAC is the critical surveillance mechanism that prevents premature chromosome segregation in the presence of unattached or misattached chromosomes. The SAC signal gets silenced after and only after the last chromosome-spindle attachment in mitosis. We previously established a model that explains the robustness of SAC silencing based on spindle-mediated spatiotemporal regulation of SAC proteins. Here, we refine the previous model, and find that robust and timely SAC silencing entails proper size scaling of mitotic spindle. This finding provides, to our knowledge, a novel, function-oriented angle toward understanding the observed spindle allometry, and the universal scaling relationship between spindle size and cell size in metazoans. In a broad sense, the functional requirement of robust SAC silencing could have helped shape the spindle assembly mechanism in evolution. PMID:27602734

  9. Protocol: using virus-induced gene silencing to study the arbuscular mycorrhizal symbiosis in Pisum sativum

    DEFF Research Database (Denmark)

    Grønlund, Mette; Olsen, Anne; Johansen, Elisabeth;

    2010-01-01

    , the available PEBV-VIGS protocols are inadequate for studying genes involved in the symbiosis with arbuscular mycorrhizal fungi (AMF). Here we describe a PEBV-VIGS protocol suitable for reverse genetics studies in pea of genes involved in the symbiosis with AMF and show its effectiveness in silencing genes...... involved in the early and late stages of AMF symbiosis....

  10. The Ebola virus VP35 protein is a suppressor of RNA silencing

    NARCIS (Netherlands)

    Haasnoot, J.; Vries, de W.; Geutjes, E.J.; Prins, M.W.; Haan, de P.; Berkhout, B.

    2007-01-01

    RNA silencing or interference (RNAi) is a gene regulation mechanism in eukaryotes that controls cell differentiation and developmental processes via expression of microRNAs. RNAi also serves as an innate antiviral defence response in plants, nematodes, and insects. This antiviral response is trigger

  11. Development of Virus-Induced Gene Expression and Silencing Vector Derived from Grapevine Algerian Latent Virus

    Directory of Open Access Journals (Sweden)

    Sang-Ho Park

    2016-08-01

    Full Text Available Grapevine Algerian latent virus (GALV is a member of the genus Tombusvirus in the Tombusviridae and infects not only woody perennial grapevine plant but also herbaceous Nicotiana benthamiana plant. In this study, we developed GALV-based gene expression and virus-induced gene silencing (VIGS vectors in N. benthamiana. The GALV coat protein deletion vector, pGMG, was applied to express the reporter gene, green fluorescence protein (GFP, but the expression of GFP was not detected due to the necrotic cell death on the infiltrated leaves. The p19 silencing suppressor of GALV was engineered to inactivate its expression and GFP was successfully expressed with unrelated silencing suppressor, HC-Pro, from soybean mosaic virus. The pGMG vector was used to knock down magnesium chelatase (ChlH gene in N. benthamaina and the silencing phenotype was clearly observed on systemic leaves. Altogether, the GALV-derived vector is expected to be an attractive tool for useful gene expression and VIGS vectors in grapevine as well as N. benthamiana.

  12. An Eastern Learning Paradox: Paradoxes in Two Korean Mathematics Teachers' Pedagogy of Silence in the Classroom

    Science.gov (United States)

    Lee, Kyeonghwa; Sriraman, Bharath

    2013-01-01

    Eastern philosophies of education such as Confucianism and Taosim advocate the use of silence in the teacher-pupil tradition of pedagogy. We investigate contemporary classrooms in Korea, and study whether teachers in Korea today incorporate this method implicitly or explicitly in their classrooms. Empirical data in the form of video-taped…

  13. A Silence That Wants to Be Heard: Suburban Korean American Students in Dialogue with Invisibility

    Science.gov (United States)

    Coombs, Dawan; Park, Hye-Young; Fecho, Bob

    2014-01-01

    Korean American students experience invisibility and silence as their culture and presence remain outwardly invisible in the mainstream culture of US high schools. This is further exacerbated by the silent response of the dominant population of the school towards these issues. Yet, to an extent, Korean American students find a sense of comfort…

  14. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis.

    NARCIS (Netherlands)

    Baarends, W.M.; Wassenaar, E.; Laan, R. van der; Hoogerbrugge, J.W.; Sleddens-Linkels, E.; Hoeijmakers, J.H.; Boer, P. de; Grootegoed, J.A.

    2005-01-01

    During meiotic prophase in male mammals, the X and Y chromosomes are incorporated in the XY body. This heterochromatic body is transcriptionally silenced and marked by increased ubiquitination of histone H2A. This led us to investigate the relationship between histone H2A ubiquitination and chromati

  15. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis.

    NARCIS (Netherlands)

    W.M. Baarends (Willy); E. Wassenaar (Evelyne); R. van der Laan (Roald); J.W. Hoogerbrugge (Jos); E. Sleddens-Linkels (Esther); J.H.J. Hoeijmakers (Jan); P. de Boer (Peter); J.A. Grootegoed (Anton)

    2005-01-01

    textabstractDuring meiotic prophase in male mammals, the X and Y chromosomes are incorporated in the XY body. This heterochromatic body is transcriptionally silenced and marked by increased ubiquitination of histone H2A. This led us to investigate the relationship between histone H2A ubiquitination

  16. Transporting silence : Design of carriers for siRNA to angiogenic endothelium

    NARCIS (Netherlands)

    Mixson, AJ; Ansari, AM; Fens, MHAM; Tang, QQ; Zhou, Q; Molema, G; Lu, PY; Scaria, PV; Storm, G; Woodle, MC

    2005-01-01

    The recently developed siRNA oligonucleotides are an attractive alternative to antisense as a therapeutic modality because of their robust, gene selective silencing of drug target protein expression. To achieve therapeutic success, however, several hurdles must be overcome including rapid clearance,

  17. Induction of Silencing Effect of Swedish Mutant Amyloid Precursor Protein by RNA interference

    Institute of Scientific and Technical Information of China (English)

    QIU Xin; CHEN Guohua; PAN Ji'an; CHEN Yu; ZHANG Suming

    2006-01-01

    Over-expression of APP and Swedish mutation could cause some familial early onset AD.In this study, a primary screening was conducted of effective small interference RNAs (siRNAs) targeted wild type APP (APPwt) and Swedish mutant APP (APPswe). One siRNA targeting APPwt and the other siRNA targeting APPswe were designed. All these siRNAs were endogenously expressed by siRNAs expressing plasmids. COS-7 cells were transiently co-transfected with APP-GFP recombinant plasmids and siRNA expression vector. The silencing effect of each siRNA was quantitatively assessed by the level of expression of green fluorescent protein (GFP). It was found that the siRNAs silenced APPwt and APPswe to different degrees. siRNA directed against APPswe was more effective in suppressing the expression of fusion gene of APPswe than that of APPwt. The silencing effect of siRNA directed against APPswe indicating allele-specific silencing property of the siRNAs. Therefore, siRNAs directed against APP play an important role both in the therapeutic study of Alzheimer disease and functional exploration of APP gene.

  18. Efficient Silencing of Endogenous MicroRNAs Using Artificial MicroRNAs in Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    Andrew L. Eamens; Claire Agius; Neil A. Smith; Peter M. Waterhouse; Ming-Bo Wang

    2011-01-01

    We report here that the expression of endogenous microRNAs (miRNAs) can be efficiently silenced in Arabidopsis thaliana (Arabidopsis) using artificial miRNA (amiRNA) technology. We demonstrate that an amiRNA designed to target a mature miRNA directs silencing against all miRNA family members, whereas an amiRNA designed to target the stem-loop region of a miRNA precursor transcript directs silencing against only the individual family member targeted.Furthermore, our results indicate that amiRNAs targeting both the mature miRNA and stem-loop sequence direct RNA silencing through cleavage of the miRNA precursor transcript, which presumably occurs in the nucleus of a plant cell during the initial stages of miRNA biogenesis. This suggests that small RNA (sRNA)-guided RNA cleavage in plants occurs not only in the cytoplasm, but also in the nucleus. Many plant miRNA gene families have been identified via sequencing and bioinformatic analysis, but, to date, only a small tranche of these have been functionally characterized due to a lack of effective forward or reverse genetic tools. Our findings therefore provide a new and powerful reverse-genetic tool for the analysis of miRNA function in plants.

  19. Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing

    Science.gov (United States)

    Seguín-Estévez, Queralt; Dunand-Sauthier, Isabelle; Lemeille, Sylvain; Iseli, Christian; Ibberson, Mark; Ioannidis, Vassilios; Schmid, Christoph D.; Rousseau, Philippe; Barras, Emmanuèle; Geinoz, Antoine; Xenarios, Ioannis; Acha-Orbea, Hans; Reith, Walter

    2014-01-01

    The activation, or maturation, of dendritic cells (DCs) is crucial for the initiation of adaptive T-cell mediated immune responses. Research on the molecular mechanisms implicated in DC maturation has focused primarily on inducible gene-expression events promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC function by inducing widespread gene-silencing remain poorly understood. Yet the termination of key functions is known to be critical for the function of activated DCs. Genome-wide analysis of activation-induced histone deacetylation, combined with genome-wide quantification of activation-induced silencing of nascent transcription, led us to identify a novel inducible transcriptional-repression pathway that makes major contributions to the DC-maturation process. This silencing response is a rapid primary event distinct from repression mechanisms known to operate at later stages of DC maturation. The repressed genes function in pivotal processes—including antigen-presentation, extracellular signal detection, intracellular signal transduction and lipid-mediator biosynthesis—underscoring the central contribution of the silencing mechanism to rapid reshaping of DC function. Interestingly, promoters of the repressed genes exhibit a surprisingly high frequency of PU.1-occupied sites, suggesting a novel role for this lineage-specific transcription factor in marking genes poised for inducible repression. PMID:25104025

  20. A Day of Silence, a Day of Truth, and a Lawsuit

    Science.gov (United States)

    Fusarelli, Bonnie C.; Eaton, Lucy E.

    2011-01-01

    This case study focuses on issues of freedom of speech and freedom of religion in public schools. It involves a rural, southern high school where a group of students participated in a Day of Silence. The school allowed the students to participate based on the principal's understanding of the students' First Amendment rights. However, the next day,…

  1. On the Grammar of Silence: The Structure of My Undocumented Immigrant Writer's Block

    Science.gov (United States)

    Ledesma, Alberto

    2015-01-01

    In this reflective essay, Alberto Ledesma explores how being undocumented can produce a particular form of writer's block. He argues that there is a pattern of predictable silences and obfuscations inherent in all undocumented immigrant autobiographies that cannot be easily negotiated when undocumented students are asked to write about "their…

  2. Hearing Silence: Toward a Mixed-Method Approach for Studying Genres' Exclusionary Potential

    Science.gov (United States)

    Randazzo, Chalice

    2015-01-01

    Traditional Rhetorical Genre Study (RGS) methods are not well adapted to study exclusion because excluded information and people are typically absent from the genre, and some excluded information is simply unrelated to the genre because of genre conventions or social context. Within genre-based silences, how can scholars differentiate between an…

  3. Transcriptional silencing and developmental reactivation of cry1Ab gene in transgenic rice

    Institute of Scientific and Technical Information of China (English)

    WU; Gang(吴刚); CUI; Hairui(崔海瑞); SHU; Qingyao(舒庆尧); YE; Gongyin(叶恭银); XIA; Yingwu(夏英武); GAO; Mingwei(高明蔚); Illimar; Altosaar; LI; Yi(李毅)

    2002-01-01

    One transgenic rice line lacking Cry1Ab expression product was screened in the progenies of Agrobacterium-transformed transgenic rice variety Zhong 8215 with a cry1Ab gene under field releasing conditions by using GUS histochemical assay and Western blot. Molecular hybridization results revealed that the cry1Ab gene was silenced in the transgenic rice variety Zhong 8215 and two copies of ubiquitin promoter were integrated into the rice genome. The silencing of cry1Ab gene in transgenic rice was found to be due to the methylation of the ubiquitin promoter as revealed by methylation analysis. Meanwhile, different concentrations of demethylation reagent 5-azacytidine combining with different treatment time were employed to treat the silenced transgenic rice seeds. The results indicated that 5-azacytidine could reactivate 8%-30% of the silenced transgenic rice plants and the expression level of the reactivated cry1Ab transgene could reach as high as 0.147% of the total soluble protein. Treatment with low concentration of 5-azacytidine(45 mg/L for 1 d and 2 d) could lead to the highest reactivation ratio and the highest expression level of the cry1Ab gene.

  4. Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis

    Directory of Open Access Journals (Sweden)

    Schlamp Cassandra L

    2010-05-01

    Full Text Available Abstract Background Silencing of normal gene expression occurs early in the apoptosis of neurons, well before the cell is committed to the death pathway, and has been extensively characterized in injured retinal ganglion cells. The causative mechanism of this widespread change in gene expression is unknown. We investigated whether an epigenetic change in active chromatin, specifically histone H4 deacetylation, was an underlying mechanism of gene silencing in apoptotic retinal ganglion cells (RGCs following an acute injury to the optic nerve. Results Histone deacetylase 3 (HDAC3 translocates to the nuclei of dying cells shortly after lesion of the optic nerve and is associated with an increase in nuclear HDAC activity and widespread histone deacetylation. H4 in promoters of representative genes was rapidly and indiscriminately deacetylated, regardless of the gene examined. As apoptosis progressed, H4 of silenced genes remained deacetylated, while H4 of newly activated genes regained, or even increased, its acetylated state. Inhibition of retinal HDAC activity with trichostatin A (TSA was able to both preserve the expression of a representative RGC-specific gene and attenuate cell loss in response to optic nerve damage. Conclusions These data indicate that histone deacetylation plays a central role in transcriptional dysregulation in dying RGCs. The data also suggests that HDAC3, in particular, may feature heavily in apoptotic gene silencing.

  5. The Spiral of Silence Ten Years Later: An Examination and Evaluation.

    Science.gov (United States)

    Salmon, Charles T.; Kline, F. Gerald

    In her model of opinion formation, Elizabeth Noelle-Neumann postulates a spiral of silence: to avoid isolation, people holding minority views either alter their ideas to conform to the majority's stance or remain silent, thus increasing the impression of the majority view's dominance. While providing a helpful integration of disparate ideas in…

  6. Post-transcriptional Gene Silencing Induced by Short Interfering RNAs in Cultured Transgenic Plant Cells

    Institute of Scientific and Technical Information of China (English)

    Wei Tang; Vanessa Samuels; Nicki Whitley; Nicole Bloom; Tinya DeLaGarza; Ronald J. Newton

    2004-01-01

    Short interfering RNA (siRNA) is widely used for studying post-transcriptional gene silencing and holds great promise as a tool for both identifying function of novel genes and validating drug targets. Two siRNA fragments (siRNA-a and -b),which were designed against different specific areas of coding region of the same target green fluorescent protein (GFP) gene, were used to silence GFP expression in cultured gfp transgenic cells of rice (Oryza sativa L.; OS), cotton (Gossypium hirsutum L.; GH), Fraser fir [Abies fraseri (Pursh) Poir; AF], and Virginia pine (Pinus virginiana Mill.; PV). Differential gene silencing was observed in the bombarded transgenic cells between two siRNAs, and these results were consistent with the inactivation of GFP confirmed by laser scanning microscopy, Northern blot,and siRNA analysis in tested transgenic cell cultures. These data suggest that siRNA-mediated gene inactivation can be the siRNA specific in different plant species. These results indicate that siRNA is a highly specific tool for targeted gene knockdown and for establishing siRNA-mediated gene silencing, which could be a reliable approach for large-scale screening of gene function and drug target validation.

  7. The Relationship between Organizational Climate and the Organizational Silence of Administrative Staff in Education Department

    Science.gov (United States)

    Pozveh, Asghar Zamani; Karimi, Fariba

    2016-01-01

    The aim of the present study was to determine the relationship between organizational climate and the organizational silence of administrative staff in Education Department in Isfahan. The research method was descriptive and correlational-type method. The study population was administrative staff of Education Department in Isfahan during the…

  8. Suffering, silence, and status: the importance and challenges of qualitative research on AIDS orphanhood.

    Science.gov (United States)

    Cheney, Kristen E

    2015-01-01

    Drawing on ethnographic fieldwork with Ugandan children affected by AIDS conducted from 2007 to 2014, this report summarizes findings of a study conducted to better understand the ways children experience orphanhood at the hands of HIV/AIDS. Three crucial, interrelated concepts emerged: suffering, silence, and status. This study explored the social context of AIDS orphanhood as both a cause of social suffering and a context for the suffering of individual children. Though problematic, silence about suffering is often due to continuing HIV/AIDS stigma in Uganda that makes one's status unspeakable, in spite of the adverse effect this has on the social order and efforts to eradicate the disease. Approaching silence as a distinct form of communication rather than an absence of it, the report considers silence's intergenerational functions, its detriments, and its consolations, in the context of HIV/AIDS-affected children's lives. In doing so, it also highlights the need for more child-centered, qualitative research on AIDS' psychosocial effects on children, despite the challenges of doing such research. PMID:25297723

  9. Interplays between Soil-Borne Plant Viruses and RNA Silencing-Mediated Antiviral Defense in Roots

    Science.gov (United States)

    Andika, Ida Bagus; Kondo, Hideki; Sun, Liying

    2016-01-01

    Although the majority of plant viruses are transmitted by arthropod vectors and invade the host plants through the aerial parts, there is a considerable number of plant viruses that infect roots via soil-inhabiting vectors such as plasmodiophorids, chytrids, and nematodes. These soil-borne viruses belong to diverse families, and many of them cause serious diseases in major crop plants. Thus, roots are important organs for the life cycle of many viruses. Compared to shoots, roots have a distinct metabolism and particular physiological characteristics due to the differences in development, cell composition, gene expression patterns, and surrounding environmental conditions. RNA silencing is an important innate defense mechanism to combat virus infection in plants, but the specific information on the activities and molecular mechanism of RNA silencing-mediated viral defense in root tissue is still limited. In this review, we summarize and discuss the current knowledge regarding RNA silencing aspects of the interactions between soil-borne viruses and host plants. Overall, research evidence suggests that soil-borne viruses have evolved to adapt to the distinct mechanism of antiviral RNA silencing in roots.

  10. Silence, pleasure and agency: Sexuality of unmarried girls in Dakar, Senegal

    NARCIS (Netherlands)

    Eerdewijk, A.H.J.M. van

    2009-01-01

    The article investigates the way unmarried Muslim girls in contemporary Dakar construct their sexuality. It explores in what way and to what extent female sexuality is being silenced, and if any, in what way pleasure and sexual agency are present in the narratives of those girls about their intimate

  11. The Shadow of Silence on the Sexual Rights of Married Iranian Women

    Directory of Open Access Journals (Sweden)

    Roksana Janghorban

    2015-01-01

    Full Text Available There has been a recent shift in the field of sexual health, representing a move away from biomedical concerns to sexual rights frameworks. However, few studies on sexuality are based on a rights framework. The unspoken nature of sexuality in Iranian culture has led to a lack of national studies on the topic. The objective of this study was to explore the perceptions and experiences of married Iranian women on sexual rights in their sexual relationships. In this grounded theory study, 37 participants (25 married women, 5 husbands, and 7 midwives were selected. Data were collected through in-depth interviews and analyzed through open, axial, and selective coding using MAXQDA software version 2007. The analysis revealed the core category of “sexual interaction in the shadow of silence.” The interrelated categories subsumed under the core category included adopting a strategy of silence, trying to negotiate sex, seeking help, and sexual adjustment. The silence originating from women’s interactions with their families and society, from girlhood to womanhood, was identified as the core concept in Iranian women’s experiences of sexual rights. A focus on husbands’ roles seems salient because they can direct or alter some learned feminine roles, especially silence regarding sexual matters, which then affects the realization of women’s sexual rights.

  12. Structure Tuning of Cationic Oligospermine-siRNA Conjugates for Carrier-Free Gene Silencing.

    Science.gov (United States)

    Nothisen, Marc; Bagilet, Jérémy; Behr, Jean-Paul; Remy, Jean-Serge; Kotera, Mitsuharu

    2016-08-01

    Oligospermine-siRNA conjugates are able to induce efficient luciferase gene silencing upon carrier-free transfection. These conjugates are readily accessible by a versatile automated chemistry that we developed using a DMT-spermine phosphoramidite reagent. In this article, we used this chemistry to study a wide range of structural modifications of the oligospermine-siRNA conjugates, i.e., variation of conjugate positions and introduction of chemical modifications to increase nuclease resistance. At first we examined gene silencing activity of a series of siRNA-tris(spermine) conjugates with and without chemical modifications in standard carrier assisted conditions. The three spermine units attached at one of the two ends of the sense strand or at the 3'-end of the antisense strand are compatible with gene silencing activity whereas attachment of spermine units at the 5'-end of the antisense strand abolished the activity. 2'-O-Methylated nucleotides introduced in the sense strand are compatible while not in the antisense strand. Thiophosphate links could be used without activity loss at the 3'-end of both strands and at the 5'-end of the sense strand to conjugate oligospermine. Consequently a series of oligospermine-siRNA conjugates containing 15 to 45 spermines units in various configurations were chosen, prepared, and examined in carrier-free conditions. Attachment of 30 spermine units singly at the 5'-end of the sense strand provides the most potent carrier-free siRNA. Longevity of luciferase gene silencing was studied using oligospermine-siRNA conjugates. Five day long efficiency with more than 80% gene expression knockdown was observed upon transfection without vector. Oligospermine-siRNA conjugates targeting cell-constitutive natural lamin A/C gene were prepared. Efficient gene silencing was observed upon carrier-free transfection of siRNA conjugates containing 20 or 30 spermine residues grafted at the 5'-end of the sense strand. PMID:27398779

  13. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation.

    Directory of Open Access Journals (Sweden)

    Kevin Pruitt

    2006-03-01

    Full Text Available The class III histone deactylase (HDAC, SIRT1, has cancer relevance because it regulates lifespan in multiple organisms, down-regulates p53 function through deacetylation, and is linked to polycomb gene silencing in Drosophila. However, it has not been reported to mediate heterochromatin formation or heritable silencing for endogenous mammalian genes. Herein, we show that SIRT1 localizes to promoters of several aberrantly silenced tumor suppressor genes (TSGs in which 5' CpG islands are densely hypermethylated, but not to these same promoters in cell lines in which the promoters are not hypermethylated and the genes are expressed. Heretofore, only type I and II HDACs, through deactylation of lysines 9 and 14 of histone H3 (H3-K9 and H3-K14, respectively, had been tied to the above TSG silencing. However, inhibition of these enzymes alone fails to re-activate the genes unless DNA methylation is first inhibited. In contrast, inhibition of SIRT1 by pharmacologic, dominant negative, and siRNA (small interfering RNA-mediated inhibition in breast and colon cancer cells causes increased H4-K16 and H3-K9 acetylation at endogenous promoters and gene re-expression despite full retention of promoter DNA hypermethylation. Furthermore, SIRT1 inhibition affects key phenotypic aspects of cancer cells. We thus have identified a new component of epigenetic TSG silencing that may potentially link some epigenetic changes associated with aging with those found in cancer, and provide new directions for therapeutically targeting these important genes for re-expression.

  14. Gene silencing in tick cell lines using small interfering or long double-stranded RNA.

    Science.gov (United States)

    Barry, Gerald; Alberdi, Pilar; Schnettler, Esther; Weisheit, Sabine; Kohl, Alain; Fazakerley, John K; Bell-Sakyi, Lesley

    2013-03-01

    Gene silencing by RNA interference (RNAi) is an important research tool in many areas of biology. To effectively harness the power of this technique in order to explore tick functional genomics and tick-microorganism interactions, optimised parameters for RNAi-mediated gene silencing in tick cells need to be established. Ten cell lines from four economically important ixodid tick genera (Amblyomma, Hyalomma, Ixodes and Rhipicephalus including the sub-species Boophilus) were used to examine key parameters including small interfering RNA (siRNA), double stranded RNA (dsRNA), transfection reagent and incubation time for silencing virus reporter and endogenous tick genes. Transfection reagents were essential for the uptake of siRNA whereas long dsRNA alone was taken up by most tick cell lines. Significant virus reporter protein knockdown was achieved using either siRNA or dsRNA in all the cell lines tested. Optimum conditions varied according to the cell line. Consistency between replicates and duration of incubation with dsRNA were addressed for two Ixodes scapularis cell lines; IDE8 supported more consistent and effective silencing of the endogenous gene subolesin than ISE6, and highly significant knockdown of the endogenous gene 2I1F6 in IDE8 cells was achieved within 48 h incubation with dsRNA. In summary, this study shows that gene silencing by RNAi in tick cell lines is generally more efficient with dsRNA than with siRNA but results vary between cell lines and optimal parameters need to be determined for each experimental system.

  15. Research on the jamming mechanism for intense light bomb by antagonizing low-light level night-vision device

    Science.gov (United States)

    Che, Jinxi; Li, Zhongmin; Zhang, Jinchun

    2013-08-01

    The low-light level night-vision device was widely applied in military and common field. The working principle of the low-light level night-vision device and radiation shine mechanism of highlight interference bomb were analysed. The tactical use way of the highlight interference bomb was briefly analysed. In addition, the computing method of flash radiation was provided. The jamming mechanism for intense light bomb by antagonizing low-light level night-vision device was analysed from the relation between surroundings illuminate and luminance of fluorescent screen, the relation between target illuminate and damage threshold of fluorescent screen and the influence on lifetime of instrument by intense light, which provided reference to study the jamming technology on the low-light level night-vision device.

  16. Identification and Antagonism Study of a Novel Chitinase-producing Bacterium Burkholderia Sp.C3 against Phytopathogenic Fungi

    Institute of Scientific and Technical Information of China (English)

    金虹; TAO Yong

    2006-01-01

    Through a modified agar well diffusion assay, antagonism of a novel chitinase-producing strain C3 against the phytopathogenic fungi including Phoma wasabiae Yokogi,Heterostrophus, Exserohilum Turcicum, Curwularia (Walk) Boed, Thantephorus cucumris, Fusarium graminearum was tested. The data showed that the crude cxtracts of strain C3 had stable antifungal activity in the range of pH 5.0 to pH 8.0. The active components were heat labile and sensitive to proteinase K. A series of experiments supported that the compound responsible for inhibitory activity appeared to be ehitinase. The 16s rDNA analysis indicated that C3 was subject to genus Burkholderia. Pbenotypic characterization of C3 was also consisted with the result of molecular identification.

  17. Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia.

    Science.gov (United States)

    Oertel, B G; Felden, L; Tran, P V; Bradshaw, M H; Angst, M S; Schmidt, H; Johnson, S; Greer, J J; Geisslinger, G; Varney, M A; Lötsch, J

    2010-02-01

    Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P CX717 than with placebo. In contrast, CX717 did not affect alfentanil-induced analgesia in either electrical or heat-based experimental models of pain. Both ventilatory depression and analgesia were reversed with 1.6 mg of naloxone. These results support the use of ampakines as selective antidotes in humans to counter opioid-induced ventilatory depression without affecting opioid-mediated analgesia. PMID:19907420

  18. Screening of 397 chemicals and development of a quantitative structure-activity relationship model for androgen receptor antagonism

    DEFF Research Database (Denmark)

    Vinggaard, Annemarie; Niemelä, Jay Russell; Wedebye, Eva Bay;

    2008-01-01

    We have screened 397 chemicals for human androgen receptor (AR) antagonism by a sensitive reporter gene assay to generate data for the development of a quantitative structure-activity relationship (QSAR) model. A total of 523 chemicals comprising data on 292 chemicals from our laboratory and data...... on 231 chemicals from the literature constituted the training set for the model. The chemicals were selected with the purpose of representing a wide range of chemical structures (e.g., organochlorines and polycyclic aromatic hydrocarbons) and various functions (e.g., natural hormones, pesticides......, plastizicers, plastic additives, brominated flame retardants, and roast mutagens). In addition, the intention was to obtain an equal number of positive and negative chemicals. Among our own data for the training set, 45.7% exhibited inhibitory activity against the transcriptional activity induced...

  19. Physiology of Sporolactobacillus strains isolated from different habitats and the indication of in vitro antagonism against Bacillus species.

    Science.gov (United States)

    Holzapfel, W H; Botha, S J

    1988-10-01

    In an ecological study only low numbers of Sporolactobacillus were found in habitats such as the faeces of herbivores, the rumen of cattle and the final waste water of an abattoir. Their presence in the final waste water of an abattoir indicates their possible association with food, and, more specifically, with meat. Differences were found in some physiological characteristics. One isolate (L2404) differed from the authentic Sporolactobacillus ATCC 15538 by its inability to ferment inulin, its growth in presence of 6.5% NaCl and in 0.2% tellurite, by the isomer(s) of lactic acid produced and the mol% G + G in the DNA. One Sporolactobacillus isolate (L2407) showed antagonism against Bacillus cereus, Bacillus cereus var, mycoides, Bacillus megaterium and Bacillus subtilis. PMID:3275317

  20. Conserved functional antagonism of CELF and MBNL proteins controls stem cell-specific alternative splicing in planarians.

    Science.gov (United States)

    Solana, Jordi; Irimia, Manuel; Ayoub, Salah; Orejuela, Marta Rodriguez; Zywitza, Vera; Jens, Marvin; Tapial, Javier; Ray, Debashish; Morris, Quaid; Hughes, Timothy R; Blencowe, Benjamin J; Rajewsky, Nikolaus

    2016-01-01

    In contrast to transcriptional regulation, the function of alternative splicing (AS) in stem cells is poorly understood. In mammals, MBNL proteins negatively regulate an exon program specific of embryonic stem cells; however, little is known about the in vivo significance of this regulation. We studied AS in a powerful in vivo model for stem cell biology, the planarian Schmidtea mediterranea. We discover a conserved AS program comprising hundreds of alternative exons, microexons and introns that is differentially regulated in planarian stem cells, and comprehensively identify its regulators. We show that functional antagonism between CELF and MBNL factors directly controls stem cell-specific AS in planarians, placing the origin of this regulatory mechanism at the base of Bilaterians. Knockdown of CELF or MBNL factors lead to abnormal regenerative capacities by affecting self-renewal and differentiation sets of genes, respectively. These results highlight the importance of AS interactions in stem cell regulation across metazoans. PMID:27502555

  1. Biochemical and metabolic profiles of Trichoderma strains isolated from common bean crops in the Brazilian Cerrado, and potential antagonism against Sclerotinia sclerotiorum.

    Science.gov (United States)

    Lopes, Fabyano Alvares Cardoso; Steindorff, Andrei Stecca; Geraldine, Alaerson Maia; Brandão, Renata Silva; Monteiro, Valdirene Neves; Lobo, Murillo; Coelho, Alexandre Siqueira Guedes; Ulhoa, Cirano José; Silva, Roberto Nascimento

    2012-07-01

    Some species of Trichoderma have successfully been used in the commercial biological control of fungal pathogens, e.g., Sclerotinia sclerotiorum, an economically important pathogen of common beans (Phaseolus vulgaris L.). The objectives of the present study were (1) to provide molecular characterization of Trichoderma strains isolated from the Brazilian Cerrado; (2) to assess the metabolic profile of each strain by means of Biolog FF Microplates; and (3) to evaluate the ability of each strain to antagonize S. sclerotiorum via the production of cell wall-degrading enzymes (CWDEs), volatile antibiotics, and dual-culture tests. Among 21 isolates, we identified 42.86% as Trichoderma asperellum, 33.33% as Trichoderma harzianum, 14.29% as Trichoderma tomentosum, 4.76% as Trichoderma koningiopsis, and 4.76% as Trichoderma erinaceum. Trichoderma asperellum showed the highest CWDE activity. However, no species secreted a specific group of CWDEs. Trichoderma asperellum 364/01, T. asperellum 483/02, and T. asperellum 356/02 exhibited high and medium specific activities for key enzymes in the mycoparasitic process, but a low capacity for antagonism. We observed no significant correlation between CWDE and antagonism, or between metabolic profile and antagonism. The diversity of Trichoderma species, and in particular of T. harzianum, was clearly reflected in their metabolic profiles. Our findings indicate that the selection of Trichoderma candidates for biological control should be based primarily on the environmental fitness of competitive isolates and the target pathogen.

  2. Draft genome sequence of Streptomyces sp. strain Wb2n-11, a desert isolate with broad-spectrum antagonism against soilborne phytopathogens

    Energy Technology Data Exchange (ETDEWEB)

    Koeberl, Martina; White, Richard A.; Erschen, Sabine; El-Arabi, Tarek F.; Jansson, Janet K.; Berg, Gabriele

    2015-08-06

    Streptomyces sp. strain Wb2n-11, isolated from native desert soil, exhibited broad-spectrum antagonism against plant pathogenic fungi, bacteria and nematodes. The 8.2 Mb draft genome reveals genes putatively responsible for its promising biocontrol activity and genes which enable the soil bacterium to directly interact beneficially with plants.

  3. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PIGF-1/VEGF heterodimers

    DEFF Research Database (Denmark)

    Eriksson, A.; Cao, R.; Pawliuk, R.;

    2002-01-01

    , the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1...

  4. Random mutagenesis defines a domain of Theiler's virus leader protein that is essential for antagonism of nucleocytoplasmic trafficking and cytokine gene expression.

    NARCIS (Netherlands)

    Ricour, C.; Borghese, F.; Sorgeloos, F.; Hato, S.V.; Kuppeveld, F.J.M. van; Michiels, T.

    2009-01-01

    The leader protein of cardioviruses, Theiler's murine encephalomyelitis virus (TMEV) and encephalomyocarditis virus (EMCV), is a multifunctional protein known to antagonize type I interferon expression and to interfere with nucleocytoplasmic trafficking of host proteins and mRNA. This protein plays

  5. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects

    DEFF Research Database (Denmark)

    Meier, Juris J; Kemmeries, Guido; Holst, Jens Juul;

    2005-01-01

    caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance...

  6. Glutamatergic dysbalance and oxidative stress in in vivo and in vitro models of psychosis based on chronic NMDA receptor antagonism.

    Directory of Open Access Journals (Sweden)

    Just Genius

    Full Text Available BACKGROUND: The psychotomimetic effects of N-methyl-D-aspartate (NMDA receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia. METHODS: The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days. In one subgroup the antipsychotic haloperidol (1 mg/kg was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats. RESULTS: Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/- 10.4% S.E.M of control; p=0.037, while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro. CONCLUSION: The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.

  7. Chiral recognition of pinacidil and its 3-pyridyl isomer by canine cardiac and smooth muscle: Antagonism by sulfonylureas

    International Nuclear Information System (INIS)

    Pinacidil, a potassium channel opener (PCO), relaxes vascular smooth muscle by increasing potassium ion membrane conductance, thereby causing membrane hyperpolarization. PCOs also act on cardiac muscle to decrease action potential duration (APD) selectively. To examine the enantiomeric selectivity of pinacidil, the stereoisomers of pinacidil (a 4-pyridylcyanoguanidine) and its 3-pyridyl isomer (LY222675) were synthesized and studied in canine Purkinje fibers and cephalic veins. The (-)-enantiomers of both pinacidil and LY222675 were more potent in relaxing phenylephrine-contracted cephalic veins and decreasing APD than were their corresponding (+)-enantiomers. The EC50 values for (-)-pinacidil and (-)-LY222675 in relaxing cephalic veins were 0.44 and 0.09 microM, respectively. In decreasing APD, the EC50 values were 3.2 microM for (-)-pinacidil and 0.43 microM for (-)-LY222675. The eudismic ratio was greater for the 3-pyridyl isomer than for pinacidil in both cardiac (71 vs. 22) and vascular (53 vs. 17) tissues. (-)-LY222675 and (-)-pinacidil (0.1-30 microM) also increased 86Rb efflux from cephalic veins to a greater extent than did their respective optical antipodes. The antidiabetic sulfonylurea, glyburide (1-30 microM), shifted the vascular concentration-response curve of (-)-pinacidil to the right by a similar extent at each inhibitor concentration. Glipizide also antagonized the response to (-)-pinacidil, but was about 1/10 as potent with a maximal shift occurring at 10 and 30 microM. Glyburide antagonized the vascular relaxant effects of 0.3 microM (-)-LY222675 (EC50, 2.3 microM) and reversed the decrease in APD caused by 3 microM (-)-LY222675 (EC50, 1.9 microM). Nitroprusside did not alter 86Rb efflux, and vascular relaxation induced by sodium nitroprusside was unaffected by sulfonylureas

  8. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    Directory of Open Access Journals (Sweden)

    Högberg Thomas

    2007-02-01

    Full Text Available Abstract Background Mast cell-derived prostaglandin D2 (PGD2, may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2, a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Methods Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. Results TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. Conclusion This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.

  9. Bilberry extract, its major polyphenolic compounds, and the soy isoflavone genistein antagonize the cytostatic drug erlotinib in human epithelial cells.

    Science.gov (United States)

    Aichinger, G; Pahlke, G; Nagel, L J; Berger, W; Marko, D

    2016-08-10

    Erlotinib (Tarceva®) is a chemotherapeutic drug approved for the treatment of pancreatic cancer and non-small cell lung cancer. Its primary mode of action is the inhibition of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Recently, RTK-inhibiting polyphenols have been reported to interact synergistically with erlotinib. Furthermore some anthocyanidins and anthocyanin-rich berry extracts have been reported to inhibit tyrosine kinases, including the EGFR, which raises the question of potential interactions with erlotinib. Polyphenol-rich preparations such as berry- or soy-based products are commercially available as food supplements. In the present study we tested a bilberry extract, its major anthocyanin and potential intestinal degradation products, as well as genistein, with respect to possible interactions with erlotinib. Cell growth inhibition was assessed using the sulforhodamine B assay, while interactions with EGFR phosphorylation were analyzed by SDS-PAGE/western blotting with subsequent immunodetection. Genistein, bilberry extract, delphinidin-3-O-glucoside and delphinidin were found to antagonize erlotinib whereas phloroglucinol aldehyde was found to enhance cytostatic effects of the drug on human epithelial A431 cells. Genistein also antagonized the EGFR inhibitory effects of erlotinib, whereas bilberry anthocyanins showed no significant interactions in this regard. Our data indicate that different polyphenols are potentially able to impair the cytostatic effect of erlotinib in vitro. Genistein interacts via the modulation of erlotinib-mediated EGFR inhibition whereas bilberry anthocyanins modulated the growth-inhibitory effect of erlotinib without affecting EGFR phosphorylation, thus indicating a different mechanism of interference. PMID:27485636

  10. The novel heteromeric bivalent ligand SB9 potently antagonizes P2Y(1) receptor-mediated responses.

    Science.gov (United States)

    Lambrecht, G; Ganso, M; Bäumert, H G; Spatz-Kümbel, G; Hildebrandt, C; Braun, K; Mutschler, E

    2000-07-01

    Effects of 6-[(4,6,8-trisulfo-1-naphthyl)iminocarbonyl-1, 3-(4-methylphenylene)iminocarbonyl-1, 3-phenylene-azo]-pyridoxal-5'-phosphate (SB9), a heterodimeric bivalent ligand consisting of pyridoxal-5'-phosphate and the suramin monomer, were studied on contractions of the rat vas deferens elicited by alpha beta-methylene ATP (alpha beta meATP; mediated by P2X(1)-like receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S mediated by P2Y(1)-like receptors), and the degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. SB9 (0.1-10 microM) antagonized contractile responses produced by alpha beta meATP or ADP beta S in a concentration-dependent manner. Schild analysis yielded linear regression lines of unit slope, indicating competitive antagonism. From the rightward shifts of the agonist concentration-response curves pA(2) values of 6.05+/-0.13 (vas deferens) and 6.98+/-0.07 (ileum) were derived. In both preparations, SB9 behaved as a slow onset, slow offset antagonist. Incubation of three oocytes in the presence of ATP produced an increase in inorganic phosphate (P(i)) over a 30-min period, which amounted to 35.1+/-1.9 microM P(i) from 100 microM ATP. SB9 (10-1000 microM) reduced this degradation (pIC(50)=4.33+/-0.10). The results illustrate that SB9 is a high-affinity P2Y(1) receptor antagonist with a remarkable selectivity for P2Y(1) vs. P2X(1) receptors (about 10-fold) and ecto-nucleotidases (447-fold). These properties make it unique among the pyridoxal-5'-phosphate and suramin derivatives reported to date.

  11. Cholinolytic antagonism to the disruptive effects of oral low doses of pyridostigmine on simple discrimination performance in rats.

    Science.gov (United States)

    Liu, W F

    1991-12-01

    We have previously reported that acute oral administration of low doses (less than or equal to 12 mg/kg) of pyridostigmine bromide (PYR) to rats resulted in a dose-dependent decrement in reinforcement rate under two different multiple schedules of response-produced water presentation, which involved motivational dysfunction rather than motor impairment and alterations in visual perception. The purpose of the present investigation was to examine further if the anticipated operant behavioral deficits of PYR are mediated by central and/or peripheral cholinergic mechanisms. Lever-press responses of male Sprague-Dawley rats were maintained under a multiple fixed-ratio GO/differential-reinforcement-of-low-rate NO GO, brightness discrimination, schedule of water reinforcement. The effects of the muscarinic antagonists atropine (ATR) and methylatropine (MAT), both at doses of 0.25, 0.5 and 1.0 mg/kg (SC), against a single oral low dose of PYR (12 mg/kg)-induced behavioral disruption were compared. ATR partially antagonized the reinforcement loss of PYR with concomitant dose-related increases in nonreinforced responses, whereas MAT completely antagonized the reinforcement loss without affecting the frequency of nonreinforced responses. These results suggest that in rats, the debilitating effects of oral PYR on operant behavior are primarily due to the stimulation of peripheral muscarinic receptors via its anticholinesterase activity. The increments of nonreinforced responses observed after coadministration of PYR with ATR may reflect a central, excitatory action of ATR which could affect the discrimination performance. The present results have practical implications for the clinical utilization of PYR in combination with the peripherally active muscarinic antagonist in situations where optimal performance is required.

  12. Analgesia and decrement in operant performance in socially defeated mice: selective cross-tolerance to morphine and antagonism by naltrexone.

    Science.gov (United States)

    Miczek, K A; Winslow, J T

    1987-01-01

    During a social confrontation between a resident and an intruder mouse, only the submissive or defeated intruder shows an opioid-mediated analgesia to which tolerance develops. We investigated the altered morphine responsiveness after different kinds of social experiences. Mice were assessed for performance of operant behavior under the control of a fixed ratio schedule of positive reinforcement as well as for the tail flick response to a heat stimulus before and after one or five consecutive social confrontations. The dose-effect curves for morphine's suppression of schedule-controlled behavior were closely similar before and after defeat in a single or in five social confrontations. However, the concurrently measured response to pain in the tail flick assay produced morphine dose-effect curves that were shifted to the right after defeat in one or five social confrontations. Four to six times higher doses of morphine were necessary to produce analgesia in mice that were defeated in five social confrontations. Naltrexone (1 mg/kg, ip) antagonized the suppressive effects of morphine (10 mg/kg, ip) on rate of responding and the analgesic effects. Naltrexone also blocked the development of analgesia in mice that were defeated for the first time in a social confrontation, but did not prevent the suppressive effects on rate of responding. Specific social experiences such as defeat in a social confrontation appear to alter endogenous opioid process that mediate analgesia; these processes differ from those that suppress positively reinforced behavior. The differential development of morphine tolerance to the analgesic effects, but not the rate-decreasing effects as well as the differential naltrexone antagonism of both effects may indicate the involvement of opioid and non-opioid mechanisms. PMID:3114797

  13. Effect of RNAi-mediated silencing of Livin gene on biological properties of colon cancer cell line LoVo.

    Science.gov (United States)

    Zou, A M; Wang, H F; Zhu, W F; Wang, F X; Shen, J J

    2014-05-16

    This study aimed to investigate the effect of RNAi-mediated silencing of the Livin gene on biological properties of the colon cancer cell line LoVo. Interference vectors pSilencer4.1-Ll and pSilencer4.1-L2 targeting the Livin gene were constructed and transfected into LoVo cells. The expression of the Livin gene was determined by RT-PCR and Western blotting. The apoptosis, cell cycle, colony formation, proliferation of LoVo cells, as well as their sensitivity to cisplatin, were detected by flow cytometry, colony formation assay and MTT. Livin mRNA and protein expression in LoVo cells could be effectively silenced by pSilencer4.1-Ll but not pSilencer4.1-L2. In the pSilencer4.1-Ll transfection group, the apoptosis rate of LoVo cells was significantly higher than in the control group (24.2 ± 3.2 vs 8.1 ± 1.4%, P LoVo colon cancer cells, inhibit cell proliferation and colony formation, induce apoptosis, and enhance sensitivity to cisplatin.

  14. Inhibition of RNA silencing by the coat protein of Pelargonium flower break virus: distinctions from closely related suppressors.

    Science.gov (United States)

    Martínez-Turiño, Sandra; Hernández, Carmen

    2009-02-01

    Viral-derived double-stranded RNAs (dsRNAs) activate RNA silencing, generating small interfering RNAs (siRNAs) which are incorporated into an RNA-induced silencing complex (RISC) that promotes homology-dependent degradation of cognate RNAs. To counteract this, plant viruses express RNA silencing suppressors. Here, we show that the coat protein (CP) of Pelargonium flower break virus (PFBV), a member of the genus Carmovirus, is able to efficiently inhibit RNA silencing. Interestingly, PFBV CP blocked both sense RNA- and dsRNA-triggered RNA silencing and did not preclude generation of siRNAs, which is in contrast with the abilities that have been reported for other carmoviral CPs. We have also found that PFBV CP can bind siRNAs and that this ability correlates with silencing suppression activity and enhancement of potato virus X pathogenicity. Collectively, the results indicate that PFBV CP inhibits RNA silencing by sequestering siRNAs and preventing their incorporation into a RISC, thus behaving similarly to unrelated viral suppressors but dissimilarly to orthologous ones.

  15. Simultaneous gene silencing of Bcl-2, XIAP and Survivin re-sensitizes pancreatic cancer cells towards apoptosis

    International Nuclear Information System (INIS)

    Pancreatic ductal adenocarcinoma shows a distinct apoptosis resistance, which contributes significantly to the aggressive nature of this tumor and constrains the effectiveness of new therapeutic strategies. Apoptosis resistance is determined by the net balance of the cells pro-and anti-apoptotic 'control mechanisms'. Numerous dysregulated anti-apoptotic genes have been identified in pancreatic cancer and seem to contribute to the high anti-apoptotic buffering capacity. We aimed to compare the benefit of simultaneous gene silencing (SGS) of several candidate genes with conventional gene silencing of single genes. From literature search we identified the anti-apoptotic genes XIAP, Survivin and Bcl-2 as commonly upregulated in pancreatic cancer. We performed SGS and silencing of single candidate genes using siRNA molecules in two pancreatic cancer cell lines. Effectiveness of SGS was assessed by qRT-PCR and western blotting. Apoptosis induction was measured by flow cytometry and caspase activation. Simultaneous gene silencing reduced expression of the three target genes effectively. Compared to silencing of a single target or control, SGS of these genes resulted in a significant higher induction of apoptosis in pancreatic cancer cells. In the present study we performed a subliminal silencing of different anti-apoptotic target genes simultaneously. Compared to silencing of single target genes, SGS had a significant higher impact on apoptosis induction in pancreatic cancer cells. Thereby, we give further evidence for the concept of an anti-apoptotic buffering capacity of pancreatic cancer cells

  16. Post-transcriptional silencing of flavonol synthase mRNA in tobacco leads to fruits with arrested seed set.

    Directory of Open Access Journals (Sweden)

    Monika Mahajan

    Full Text Available Flavonoids are synthesized by phenylpropanoid pathway. They are known to participate in large number of physiological and biochemical processes in plants. Parthenocarpy and male sterility has earlier been reported by silencing chalcone synthase (CHS encoding gene. Silencing of CHS has blocked the synthesis of most of useful flavonoids including flavan-3-ols and flavonols. Also, these studies could not identify whether parthenocarpy/male sterility were due to lack of flavan-3-ols or flavonols or both. Flavonol synthase (FLS is an important enzyme of flavonoid pathway that catalyzes the formation of flavonols. In this article, we propose a novel strategy towards the generation of seedless or less-seeded fruits by downregulation of flavonol biosynthesis in tobacco (Nicotiana tabacum cv Xanthi through post-transcriptional gene silencing (PTGS of FLS encoding mRNA. The FLS silenced lines were observed for 20-80% reduction in FLS encoding gene expression and 25-93% reduction in flavonol (quercetin content. Interestingly, these FLS silenced tobacco lines also showed reduction in their anthocyanidins content. While the content of flavan-3-ols (catechin, epi-catechin and epi-gallocatechin was found to be increased in FLS silenced lines. The delayed flowering in FLS silenced lines could be due to decrease in level of indole acetic acid (IAA at apical region of their shoots. Furthermore, the pollen germination was hampered and pollens were unable to produce functional pollen tube in FLS silenced tobacco lines. Pods of FLS silenced lines contained significantly less number of seeds. The in vitro and in vivo studies where 1 µM quercetin was supplied to germination media, documented the restoration of normal pollen germination and pollen tube growth. This finding identified the role of flavonols particularly quercetin in pollen germination as well as in the regulation of plant fertility. Results also suggest a novel approach towards generation of seedless

  17. Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Curry, Merril C.; Peters, Amelia A. [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia); Kenny, Paraic A. [Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461 (United States); Roberts-Thomson, Sarah J. [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia); Monteith, Gregory R., E-mail: gregm@uq.edu.au [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia)

    2013-05-10

    Highlights: •Some clinical breast cancers are associated with MCU overexpression. •MCU silencing did not alter cell death initiated with the Bcl-2 inhibitor ABT-263. •MCU silencing potentiated caspase-independent cell death initiated by ionomycin. •MCU silencing promoted ionomycin-mediated cell death without changes in bulk Ca{sup 2+}. -- Abstract: The mitochondrial calcium uniporter (MCU) transports free ionic Ca{sup 2+} into the mitochondrial matrix. We assessed MCU expression in clinical breast cancer samples using microarray analysis and the consequences of MCU silencing in a breast cancer cell line. Our results indicate that estrogen receptor negative and basal-like breast cancers are characterized by elevated levels of MCU. Silencing of MCU expression in the basal-like MDA-MB-231 breast cancer cell line produced no change in proliferation or cell viability. However, distinct consequences of MCU silencing were seen on cell death pathways. Caspase-dependent cell death initiated by the Bcl-2 inhibitor ABT-263 was not altered by MCU silencing; whereas caspase-independent cell death induced by the calcium ionophore ionomycin was potentiated by MCU silencing. Measurement of cytosolic Ca{sup 2+} levels showed that the promotion of ionomycin-induced cell death by MCU silencing occurs independently of changes in bulk cytosolic Ca{sup 2+} levels. This study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways. MCU inhibitors may be a strategy to increase the effectiveness of therapies that act through the induction of caspase-independent cell death pathways in estrogen receptor negative and basal-like breast cancers.

  18. Post-transcriptional silencing of flavonol synthase mRNA in tobacco leads to fruits with arrested seed set.

    Science.gov (United States)

    Mahajan, Monika; Ahuja, Paramvir Singh; Yadav, Sudesh Kumar

    2011-01-01

    Flavonoids are synthesized by phenylpropanoid pathway. They are known to participate in large number of physiological and biochemical processes in plants. Parthenocarpy and male sterility has earlier been reported by silencing chalcone synthase (CHS) encoding gene. Silencing of CHS has blocked the synthesis of most of useful flavonoids including flavan-3-ols and flavonols. Also, these studies could not identify whether parthenocarpy/male sterility were due to lack of flavan-3-ols or flavonols or both. Flavonol synthase (FLS) is an important enzyme of flavonoid pathway that catalyzes the formation of flavonols. In this article, we propose a novel strategy towards the generation of seedless or less-seeded fruits by downregulation of flavonol biosynthesis in tobacco (Nicotiana tabacum cv Xanthi) through post-transcriptional gene silencing (PTGS) of FLS encoding mRNA. The FLS silenced lines were observed for 20-80% reduction in FLS encoding gene expression and 25-93% reduction in flavonol (quercetin) content. Interestingly, these FLS silenced tobacco lines also showed reduction in their anthocyanidins content. While the content of flavan-3-ols (catechin, epi-catechin and epi-gallocatechin) was found to be increased in FLS silenced lines. The delayed flowering in FLS silenced lines could be due to decrease in level of indole acetic acid (IAA) at apical region of their shoots. Furthermore, the pollen germination was hampered and pollens were unable to produce functional pollen tube in FLS silenced tobacco lines. Pods of FLS silenced lines contained significantly less number of seeds. The in vitro and in vivo studies where 1 µM quercetin was supplied to germination media, documented the restoration of normal pollen germination and pollen tube growth. This finding identified the role of flavonols particularly quercetin in pollen germination as well as in the regulation of plant fertility. Results also suggest a novel approach towards generation of seedless

  19. Molecular deregulation induced by silencing of the high mobility group protein A2 gene in retinoblastoma cells

    OpenAIRE

    Venkatesan, Nalini; Krishnakumar, Subramanian; Deepa, Perinkulam Ravi; Deepa, Murali; Khetan, Vikas; Reddy, M. Ashwin

    2012-01-01

    Aim To explore the molecular mechanisms deregulated by high mobility group protein A2 (HMGA2) gene silencing in retinoblastoma (RB) cells. Methods Synthetic anti-HMGA2 short interfering RNA (siRNA) was used to silence the HMGA2 gene in cultured Y79 RB cells that were subjected to whole genome microarray analysis. The expression of differentially regulated key genes was confirmed with quantitative reverse-transcriptase polymerase chain reaction (qRT–PCR) in post-silenced RB cell lines (Y79 and...

  20. A Novel AT-Rich DNA Recognition Mechanism for Bacterial Xenogeneic Silencer MvaT.

    Directory of Open Access Journals (Sweden)

    Pengfei Ding

    2015-06-01

    Full Text Available Bacterial xenogeneic silencing proteins selectively bind to and silence expression from many AT rich regions of the chromosome. They serve as master regulators of horizontally acquired DNA, including a large number of virulence genes. To date, three distinct families of xenogeneic silencers have been identified: H-NS of Proteobacteria, Lsr2 of the Actinomycetes, and MvaT of Pseudomonas sp. Although H-NS and Lsr2 family proteins are structurally different, they all recognize the AT-rich DNA minor groove through a common AT-hook-like motif, which is absent in the MvaT family. Thus, the DNA binding mechanism of MvaT has not been determined. Here, we report the characteristics of DNA sequences targeted by MvaT with protein binding microarrays, which indicates that MvaT prefers binding flexible DNA sequences with multiple TpA steps. We demonstrate that there are clear differences in sequence preferences between MvaT and the other two xenogeneic silencer families. We also determined the structure of the DNA-binding domain of MvaT in complex with a high affinity DNA dodecamer using solution NMR. This is the first experimental structure of a xenogeneic silencer in complex with DNA, which reveals that MvaT recognizes the AT-rich DNA both through base readout by an "AT-pincer" motif inserted into the minor groove and through shape readout by multiple lysine side chains interacting with the DNA sugar-phosphate backbone. Mutations of key MvaT residues for DNA binding confirm their importance with both in vitro and in vivo assays. This novel DNA binding mode enables MvaT to better tolerate GC-base pair interruptions in the binding site and less prefer A tract DNA when compared to H-NS and Lsr2. Comparison of MvaT with other bacterial xenogeneic silencers provides a clear picture that nature has evolved unique solutions for different bacterial genera to distinguish foreign from self DNA.